WO2008072682A1 - Imidazo[1,2-b]pyridazine derivative - Google Patents

Imidazo[1,2-b]pyridazine derivative Download PDF

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WO2008072682A1
WO2008072682A1 PCT/JP2007/073993 JP2007073993W WO2008072682A1 WO 2008072682 A1 WO2008072682 A1 WO 2008072682A1 JP 2007073993 W JP2007073993 W JP 2007073993W WO 2008072682 A1 WO2008072682 A1 WO 2008072682A1
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group
amino
pyridazine
imidazo
alkoxy
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PCT/JP2007/073993
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French (fr)
Japanese (ja)
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Takanori Yasukochi
Shin Iimura
Yoshiyuki Yoneda
Hiroki Shimizu
Tomonori Yamasaki
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Daiichi Sankyo Company, Limited
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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Definitions

  • the present invention relates to a novel TNF-a production inhibitor having an imidazo [1,2-b] pyridazine skeleton.
  • TNF-a Tumor necrosis factor alpha
  • TNF-a diseases associated with overproduced TNF-a include rheumatoid arthritis, Beech's disease, allergic dermatitis, atopic dermatitis, bronchial asthma, sepsis, inflammatory bowel disease, psoriasis, thrombosis, Inflammatory diseases such as hepatitis, diabetes, chronic obstructive pulmonary disease, cerebral infarction and / or autoimmune diseases have been reported. Therefore, a drug exhibiting an inhibitory effect on TNF ⁇ production is expected to be useful as a therapeutic and / or prophylactic agent for various inflammatory diseases and autoimmune diseases.
  • an anilinopyrimidine derivative has been used as a compound having a TNF-a production inhibitory action.
  • Patent Document 1 imidazo [1,2-a] quinoxaline derivative (Non-patent Document 2), 1,4 dihydro 2H pyrido [2,3-d] [l, 3] oxazine 2-one derivative (Non-Patent Document 2) 3), 1 (pyrazole 1-yl) 3- (naphthalene 1-yl) urea derivative (Non-patent document 4), 4 Pheninore 1 5 pyridinole 1, 3 thiazole derivative (Non-patent document 5) 2 Phenyl-3- (pyridine 4-yl) 4- (1, 2, 3, 6 tetrahydropyridine 4-yl) 1 H pyrrole derivative (Non-patent document 6) etc. have been reported. Further, there is a demand for novel low-molecular-weight TNF-a inhibitor compounds that have excellent effects, can be administered orally with few side effects, and have long-lasting action.
  • Patent Document 1 Special Table 2004—523479
  • Patent Document 2 International Publication No. 2005/066177 Pamphlet
  • Patent Document 3 US Patent Application Publication No. 2004/0067948
  • Patent Document 4 International Publication No. 2007/013673
  • Patent Document 5 International Publication No. 2007/025090
  • Patent Document 6 US Patent Application Publication No. 2007/0093490
  • Non-Patent Document 1 Exp. Opin. Invest. Drugs, 2000, 9: 103.
  • Non-Patent Document 2 J. Biol. Chem., 278 (3), 1450 1456 (2003).
  • Non-Patent Document 3 Br. J. Pharmacol., 145 (2), 178-192 (2005),
  • Non-Patent Document 4 J. Med. Chem., 46 (22), 4676-4686 (2003).
  • Non-Patent Document 5 J. Med. Chem., 48 (19), 5966-5979 (2005).
  • Non-Patent Document 6 Eu. J. Pharmacol., 506, 285-295 (2005).
  • Non-Patent Document 7 J. Med. Chem., 48 (24), 7604-7614 (2005).
  • Non-Patent Document 8 J. Med. Chem., 46 (20), 4333-4341 (2003).
  • Non-Patent Document 9 J. Med. Chem., 44 (3), 350-361 (2001).
  • R 1 represents a hydrogen atom or a C 1 -C 6 alkyl group
  • R 2 represents an optionally substituted C1-C6 alkyl group or C3-C7 cycloalkyl group
  • Ring A represents a benzene ring or a 5- or 6-membered aromatic heterocycle
  • X is a hydrogen atom, or the same or different, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a hydroxy acid Group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group, C1-C6 anorecoxy C1-C6 alkoxy group, carboxy group, C1-C6 alkoxycarbonyl group, cyano group, force rumoyl group, N-mono (C1-C6 alkyl) ) Force rubermoyl group, N, N-di (C1-C6 alkyl) force rubermoyl group, amino group, mono (C1-C6 alkyl) amino group, di (C1-C6 alkyl) amino group, C1-C6 alkylthio group 1 to 3 groups selected from the group consisting
  • Y is the following formula (a) to or (V)
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3v are the same--or different and represent a hydrogen atom or a C1-C6 alkyl group,
  • R 4e , R 4f and R 4g are the same or different and are a hydrogen atom, a C1-C6 alkyl group, a halogeno C;! -C6 alkanoleno group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkyl group, C 3 to C 7 cycloalkyl C;! To C 6 alkyl group or phenyl C;!
  • the phenyl group of this phenyl C1 to C6 alkyl group is a halogeno group, a C1 to C6 alkenyl group, a hydroxyl group and C1 1 to 3 groups may be substituted with a group selected from the group consisting of -C6 alkoxy groups).
  • R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10b and R ub are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 anorequinole group, a halogeno C1 -C6 alkyl group, C1-C6 alkyloxy, C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy C1-C6 alkoxy group,
  • R 13l, R 13j, R 13v, R 14c, R 14d, R 14e, R 14f , R 14g , R 14h , R 14l , R 14j and R 14v are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 arnolequinole group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 An alkyl group, a hydroxyl group, a C1-C6 alkoxy group, a halogeno C1-C6 alkoxy group or a C1-C6 alkoxy C1-C6 alkoxy group, and k, 1, m, n, o and p are 0, 1 or 2, respectively.
  • Q represents 1 or 2
  • V represents a morpholino group.
  • the present invention provides the following (1) to (5)
  • TNF-a production inhibitor comprising a compound represented by the above general formula (I) as an active ingredient
  • a therapeutic and / or prophylactic agent for inflammatory diseases and / or autoimmune diseases comprising the compound represented by the general formula (I) as an active ingredient;
  • a therapeutic agent for rheumatoid arthritis comprising a compound represented by the above general formula (I) as an active ingredient;
  • the imidazo [1, 2-b] pyridazine derivative of the present invention suppresses the production of TNF-a by oral administration, various diseases caused by TNF ⁇ production, such as inflammatory diseases such as rheumatoid arthritis, etc. And / or enables prevention and / or treatment of autoimmune diseases.
  • various diseases caused by TNF ⁇ production such as inflammatory diseases such as rheumatoid arthritis, etc. And / or enables prevention and / or treatment of autoimmune diseases.
  • C1-C6 alkyl group refers to a monovalent group consisting of linear or branched saturated hydrocarbons having carbon number;! -6, for example, methyl group, ethyl Group, n-propyl group, isopropyl group, n-butyl group, 1-methyl-n-propyl group, 2-methyl-n-propyl group, ter-butinore group, n-pentinole group, 1-methylenole n-butinore group, 2-methinole n-butinore group, 3 Methyl-n butyl group, 1,1 dimethyl-n propyl group, 2,2 dimethyl-n propyl group, 1,2-dimethyl-n propyl group, 1-ethyl-n propyl group, n-hexyl group, 1-methyl-n pentyl group, 2 Methyl-n pentyl group, 3 methylolene n-pentyl group, 4-methyl-n-pent
  • the C3 to C7 cycloalkyl group refers to a monovalent group formed from a cyclic saturated hydrocarbon ring having 3 to 7 carbon atoms, and includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexane.
  • a xyl group and a cycloheptyl group are mentioned.
  • the 5- or 6-membered aromatic heterocycle refers to an aromatic heterocycle containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as constituent elements of the ring.
  • Examples of the 5- or 6-membered aromatic heterocycle include a pyrrole ring, a furan ring, a thiophene ring, a pyrazonole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a pyridine ring, a pyridazine ring, and a pyrimidine ring. Examples thereof include a pyrazine ring.
  • the halogeno group refers to a fluoro group, a black mouth group, a bromo group and an iodo group.
  • the halogeno C1-C6 alkyl group means a C1-C6 alkyl group having the above-mentioned halogeno group as a substituent, and the number of halogeno groups may be one or two or more.
  • the types of each halogeno group in the case of 2 or more may be the same or different.
  • halogeno C1-C6 alkyl group examples include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1 fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethynole group, a 2-bromoethyl group, a (1,1-difluoro) ethyl group, (1,2, -difluoro) ethyl group, (2,2,2--Lifnore talent) Uchinole group, (1,1,2,2-Terafugnole mouthpiece) Tuchinole group, (1,1,2,2, 2,2-pentafluoro) ethyl group, 1 fluoropropyl group, 1,1-difluoropropyl group, 2,2 difluoropropyl group, 3 fluoro-n-propyl group, (3, 3, 3 trifluoro) -n-propyl group, 4 Flu
  • the C1-C6 alkoxy group refers to a C1-C6 alkyloxy group formed from the above-mentioned C1-C6 alkyl group, and includes, for example, a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group.
  • n-butoxy group 1-methyl-n-propoxy group, 2-methyl-n Xyl group, tert butoxy group, n pentyloxy group, 1-methyl-n butoxy group, 2-methyl-n-butoxy group, 3-methyl-n-butoxy group, 1,1 dimethyl-n-propoxy group, 2,2-dimethylenole n propoxy Group, 1,2-dimethylolene n propoxy group, 1 ethyl n propoxy group, n hexyloxy group, 1-methyl n pentyloxy group, 2 methyl n pentyloxy group, 3 methyl n pentyloxy group, 4-methyl n pentyloxy group, 1, 1 Dimethyl-n butoxy group, 2,2-Dimethyl-n butoxy group, 3,3-Dimethylolene butoxy group, 1,2-Dimethylolene n-Butoxy group, 1,3 Dimethylolene n-Butoxy group, 2,3 Dimethylolene n-Butoxy group, 1 -Ethyloxy
  • 1 to 6 alkyloxy 1 to 6 alkyl groups refers to a C1-C6 alkyl group substituted by one of the above C1-C6 alkoxy groups, and include, for example, a methoxymethyl group, ethoxymethylol Group, n propoxymethyl group, isopropoxymethyl group, n butoxymethyl group, tert-butoxymethyl group, n-pentyloxymethyl group, n-hexyloxymethyl group, 1-methoxychetyl group, 2 methoxyethyl group, 2 List ethoxyethyl, 3-methoxy-n-propyl, 3-ethoxy-n-propyl, 4-methoxy-n-butyl, 4-ethoxy-n-butyl, 5-methoxy-n-pentyl and 6-methoxy-n-hexyl. Touch with force S.
  • the halogeno C1-C6 alkoxy group is a C1-C6 alkyloxy group having the above-mentioned halogeno group as a substituent, and the number of halogeno groups is one or two or more.
  • the type of each halogeno group in the case of two or more may be the same or different.
  • halogeno C1-C6 alkoxy group examples include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1 fluoroethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group, (1, 1-difluoro) ethoxy group, (1,2-difluoro) ethoxy group, (2,2,2-trifluoro) ethoxy group, (1,1,2,2,2-tetrafluoro) ethoxy group, (1,1, 2, 2, 2-pentafluoro mouth) ethoxy group, 1 fluoropropoxy n propoxy group, (3, 3, 3-trifunoleo mouth) n propoxy group, 4-funoleolone n Butoxy group, (4, 4, 4 trifluoro) -n-butoxy group, 5-fluoro-n-pentynoleoxy group, (5, 5, 5,
  • 1 to 6 alkyloxy 1 to 6 alkoxy groups are C1-C6 alkyloxy groups substituted by one of the above-mentioned C1-C6 alkoxy groups, such as methoxymethoxy group, Xymethoxy group, 2 methoxyethoxy group, 2 ethoxyethoxy group, 3 methoxy n propoxy group, 3-ethoxy n propoxy group, 4-methoxy n butoxy group, 4 ethoxy n butoxy group, 5-methoxy n pentyloxy group and 6— A methoxy-n-hexyloxy group and the like can be mentioned.
  • N mono (C1-C6 alkyl) rubamoyl group is a rubamoyl group in which one hydrogen atom on the nitrogen atom of the rubamoyl group is substituted with one of the above C1-C6 alkyl groups.
  • N (methyl) force rubamoyl group N (ethyl) force rubamoyl group, N— (n-propyl) force rubamoyl group, N (isopropyl) force rubamoyl group, N— (n butyl) force norberamoyl group, N ( Isobutyl) -powered rubermoyl group, N- (tert-butyl) -powered rubermoyl group, N- (n-pentyl) -powered rubermoyl group, and N- (n-hexyl) -powered rubermoyl group.
  • N, N di (C1-C6 alkyl) force rubamoyl group, the hydrogen atom on the nitrogen atom of force rubamoyl group is the same or different, and is substituted by the above C1-C6 alkyl group
  • the mono (C1-C6 alkyl) amino group means an amino group substituted by one of the above-mentioned C1-C6 alkyl groups, for example, methylamino group, ethylamino group, n-propylamino group, And isopropylamino group, n-butylamino group, (2-methyl-n-butyl) amino group, tert-butylamino group, n-pentylamino group and n-hexylamino group.
  • the C1-C6 alkylthio group represents a C1-C6 alkylthio group formed from the above-mentioned C1-C6 alkyl group.
  • a methylthio group, an ethylthio group, an n-propinoretio group, an isopropylthio group, an n examples include butylthio group, 2-methyl-n butylthio group, tert butylthio group, n pentylthio group, and n hexylthio group.
  • Examples of the C1-C6 alkylsulfonyl group include a methanesulfonyl group, ethanesnorehoninore group, n-propinolesnorehoninore group, isopropinoresnorehoninore group, n-butinoresnorehoninore group, 2-methinoleen n Examples include butinolesnorehoninole group, tertbutinoresnorehoninole group, npentylsulfonyl group, nhexylsulfonyl group and the like.
  • C3-C7 cycloalkyl refers to a C1-C6 alkyl group substituted by one of the above C3-C7 cycloalkyl groups, such as a cyclopropylmethyl group, 2-cyclopropyl Ethyl group, 3-cyclopropyl n-propyl group, 4-cyclopropinole n butyl group, 5-cyclopropyl-n-pentyl group, 6-cyclopropyl-n hexyl group, cyclobutylmethyl group, 2 cyclobutyl Ethyl group, 3 cyclobutyl-n propyl group, 4-cyclobutyl-n butyl group, 5-cyclobutyl-n pentyl group, 6 cyclobutyl-n hexyl group, cyclopentylmethyl group, 2 cyclopentylethyl group, 3-cyclopentyl-n propyl
  • a 4- to 7-membered nitrogen-containing aliphatic heterocyclic ring includes at least one nitrogen atom as an element constituting the ring, and is further selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
  • a 4- to 7-membered nitrogen-containing aliphatic heterocyclic ring which may contain one atom is shown.
  • Examples of the 4- to 7-membered nitrogen-containing aliphatic heterocycle include azetidine ring, pyrrolidine ring, oxazolidine ring, oxazoline ring, thiazolidine ring, imidazolidine ring, piperidine ring, piperazine ring, morpholine ring, and thiomorpholine ring. , Homopiperidine ring, [1,4] diazepan ring, [1,4] oxazepan ring, and [1,4] thiazepan ring.
  • the morpholino group represents a 2 monomorpholinole group, a 3 morpholinyl group or a 4 morpholinyl group.
  • the C1-C6 alkyl group which may have a substituent represents an unsubstituted or substituted C1-C6 alkyl group, and the substituted C1-C6 alkyl group is the same or different,
  • a 5- or 6-membered aromatic heterocyclic group (the aromatic heterocyclic ring of this aromatic heterocyclic group is composed of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group.
  • 1 to 3 groups may be substituted with a group selected from the group), a 4- to 7-membered aliphatic heterocyclic group (the aliphatic heterocyclic group of this aliphatic heterocyclic group is a halogeno group, C1-C6 alkyl) 1 to 3 groups may be substituted with a group selected from the group consisting of a group, a hydroxyl group and a C1-C6 alkoxy group 4- to 7-membered aliphatic heterocyclic group—CO group (this aliphatic heterocyclic group is a group selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group) 1 to 3 may be substituted), hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group, C3-C7 cycloalkyloxy group, phenyl C1-C6 alk
  • Amino group mono (C1-C6 alkyl) amino group, di (C1-C6 alkyl) amino group, C2-C6 alkanoylamino group, benzoylamino group (the benzoyl group of this benzoylamino group is a halogeno group, 1 to 3 groups may be substituted with a group selected from the group consisting of C1-C6 anolenoquinole group, hydroxyl group and C1-C6 alkoxy group), benzenoreamino group (the benzyl group of this benzylamino group is a halogeno group, C1 1 to 3 groups may be substituted with a group selected from the group consisting of a C6-anolequinole group, a hydroxyl group, and a C1-C6 alkoxy group.), C1-C6 alkylthio group, C1-C6 alkylsulfinyl group, C1- A C6 al
  • 1 to 3 groups may be substituted.
  • Phenylsulfinyl group (the phenylsulfinyl group is composed of a halogeno group, a C1-C6 alkanoleno group, a hydroxyl group, and a C1-C6 alkoxy group).
  • 1 to 3 groups may be substituted with a group selected from the group), and a phenylsulfonyl group (the phenylsulfonyl group of this phenylsulfonyl group is a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group).
  • the 5- or 6-membered aromatic heterocyclic group is a monovalent group formed from the above-mentioned 5- or 6-membered aromatic heterocyclic ring.
  • a pyrrolyl group (1 pyrrolyl group, 2 —Pyrrolyl group or 3 pyrrolyl group), furyl group (2 furyl group or 3 furyl group), phenyl group (2 phenyl group or 3 phenyl group), pyrazolyl group (1 Biazolinole group, 3-pyrazolyl group or 4-pyrazolyl group), imidazolyl group (1 imidazolino group, 2 imidazolyl group or 4 imidazolyl group), oxazolyl group (2 oxazolyl group, 4-oxazolyl group or 5-oxazolyl group) Group), isoxazolyl group (3-isoxazolyl group, 4 isoxazolyl group or 5-isoxazolyl group)), thiazolyl group (2 thiazolyl group (2
  • a 4- to 7-membered aliphatic heterocyclic group is a 4- to 7-membered ring containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring constituent elements. Represents a monovalent group formed from an aliphatic complex ring.
  • Examples of the 4- to 7-membered aliphatic heterocyclic group include azetidyl group (indicating 1-azetidyl group, 2-azetidyl group or 3-azetidyl group), oxetanyl group (indicating 2-oxetanyl group or 3-oxetanyl group), and chetanyl.
  • Tetrahydrothienyl group (indicating 2 tetrahydrothiphenyl group or 3 tetrahydrothienyl group), 1,1-dioxotetrahydro 1-to- 6 -thiophenyl group [2- (1,1, -dioxo-one] tetrahydro one l-lambda 6 Chiofueniru) group or 3- (1, 1-Jiokiso one tetra Hidoro 1 one It shows the 6 Chiofueniru) group.
  • Oxazolidinyl group (represents 2-oxazolidinyl group, 3-oxazolidinyl group, 4 oxazolidinyl group or 5-oxazolidinyl group), oxazolinyl group (2 oxazolinyl group, 3 oxazolinyl group, 4 oxazolinyl group or 5 oxazolinyl group or 5 oxazolinyl group Group), thiazolidinyl group (represents 2 thiazolidinyl group, 3-thiazolidinyl group, 4 thiazolidinyl group or 5-thiazolidinyl group), imidazolidinyl group (1 imidazolidinyl group, 2-imidazolidinyl group or 4 imidazolidinyl group.
  • Piperidinyl group (represents 1-piperidinyl group, 2-piperidinyl group, 3-piperidinyl group or 4-piperidinyl group), tetrahydrobiranyl group (2-tetrahydrobiranyl group, 3-tetrahydrobiranyl group or 4-tetrahydroviranyl group) Indicates the group ), Tetrahydrothiopyranyl group (represents 2 tetrahydrothiopyranyl group, 3 tetrahydrothiopyranyl group or 4-tetrahydrothiopyranyl group), piperazinyl group (1-piperazinyl group, 2 piperazinyl group or 3 piperazinyl group) ), Morpholinyl group (represents 4 morpholinyl group, 2 morpholinyl group or 3 morpholinyl group), thiomorpholinyl group (4 thiomorpholinyl group, 2 thiomorpholinyl group or 3 thiomonoreylene
  • [1, 4] dioxanyl group (2— [1,4] dioxanyl group or 3- [1,4] dioxanyl group), [1,4] oxanthanyl group (2 -— [1,4] oxanthia 2 or 3 [1, 4] oxathiadiyl group), homopiperidinyl group (1 homopiperidinyl group, 2 homopiperidinyl group, 3 homopiperidinyl group or 4 homopiperidinyl group), oxepanyl group (2 oxepanyl group) Group, 3 oxepanyl group or 4 oxepanyl group), chepanyl group (2 chepanyl group, 3 chepanyl group or 4 chepanyl group), [1,4] diazepanyl group (1 [1,4] diazepanyl group , 2- [1,4] diazepanyl group or 3- [1,4] diazepanyl group), [1,4] oxazepan
  • [1,4] thiazepanyl group (representing 4 [1,4] thiazepanyl group, 2- [1,4] thiazepanyl group or 3- [1,4] thiazepanyl group), etc. I'll do it.
  • 4- to 7-membered aliphatic heterocyclic group CO group refers to a group formed from the above 4- to 7-membered aliphatic heterocyclic group and a carbonyl group.
  • the C3 to C7 cycloalkyloxy group refers to a C3 to C7 cycloalkyloxy group formed from the above C3 to C7 cycloalkyl group.
  • phenyl C1-C6 alkoxy group refers to a C1-C6 alkyloxy group substituted with a phenyl group, for example, a benzyloxy group, a 2-phenylethoxy group, a 1-phenylethoxy group. 3 phenylpropoxy group, 2 phenylpropoxy group, 4 phenyl-n-butoxy group, 5-phenyl n-pentyloxy group, 6-phenyl n-hexyloxy group and the like.
  • a C2-C6 alkanoylamino group is an amino substituted with an alkanoyl group formed from a linear or branched alkyl group having carbon number; Groups such as acetylamino groups, n-propionylamino groups, n-butyrylamino groups, isobutyrylamino groups, tert-butyrylamino groups, n-pentanoylamino groups, (3-methyl) n-butyrylamino groups, n-hexanoylamino groups, Examples include (4,4-dimethyl) n butyrylamino group and (5-methyl) n pentanoylamino group.
  • C1-C6 alkyl sulfiel group for example, methyl sulfiel group, Ethinolesno refininole group, n propino lesno refinino group, isopropino les no refinino group, n-butino les no refinino group, 2-methino ree n butino les no refinino group, tert butino les nore fiel Group, n pentyl sulfier group, n hexyl sulfier group and the like.
  • a phenyl C1 C6 alkyl group refers to a C1 C6 alkynol group in which one phenyl group is substituted.
  • a benzyl group a 2-phenylethyl group, a 1-phenylethyl group, a 3-phenylenoyl-propynol group.
  • 2-phenolino-propynole group 4-phenolino-butylyl group, 5-phenolinopentyl group, 6-phenolenohexyl group, etc.
  • the 5- or 6-membered aromatic heterocyclic group C1 C6 alkyl group refers to a C1 C6 alkyl group substituted by one of the 5- or 6-membered aromatic heterocyclic group, for example, Pyrrolylmethylol group, furylmethyl group, chenylmethyl group, pyrazolylmethyl group, imidazolylmethyl group, oxazolylmethyl group, isoxazolylmethyl group, thiazolylmethyl group, isothiazolylmethyl group, pyridylmethyl group, pyridazinylmethyl Group, pyrimidinylmethyl group, birazinylmethyl group, 2- (pyrrolyl) ethyl group, 2- (furyl) ethyl group, 2- (chenyl) ethyl group, 2- (virazolyl) ethyl group, 2- (imidazolyl) ethyl group 2- (oxazolyl) ethyl group, 2- (pyrrolylmethyl
  • 4- to 7-membered aliphatic heterocyclic group-1- to 6-alkyl group is a C1-C6 alkyl substituted with one of the above-mentioned 4- to 7-membered aliphatic heterocyclic group Indicates a group.
  • a 4- to 7-membered aliphatic heterocyclic group 1 to 6-alkyl group refers to the above C 1 substituted with one of the above 4 to 7-membered aliphatic heterocyclic CO groups. -C6 alkyl group is shown.
  • Hydroxy C1-C6 alkyl group means the above C1-C6 alkyl group substituted by one hydroxyl group.
  • the phenoxy C1-C6 alkyl group refers to the above-mentioned C1-C6 alkyl group substituted by one phenoxy group.
  • Amino C1-C6 anoleno group refers to the above C1-C6 alkino group substituted with one amino group.
  • the C2 to C6 alkanoylamino-C1 to C6 alkyl group refers to the above C1 to C6 alkyl group substituted with one of the above C2 to C6 alkanolamino groups.
  • 1 to 6 alkylthio 1 to 6 alkyl groups represent the above C 1 to C 6 alkyl groups substituted by one of the above C 1 to C 6 alkylthio groups.
  • 1 to 6 alkylsulfonyl refers to the above C 1 to C 6 alkyl group substituted by one of the above C1 to C6 alkylsulfonyl groups. .
  • R 1 represents a hydrogen atom or a C1-C6 alkyl group, preferably a hydrogen atom or a C1-C4 alkyl group.
  • R 2 represents a C1-C6 alkyl group or a C3-C7 cycloalkyl group which may have a substituent.
  • Ring A represents a benzene ring or a 5- or 6-membered aromatic heterocycle, and is a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an oxazole ring, a thiazole ring, a pyridine ring, Pyridazine ring, pyrimidine ring and pyrazine ring are preferred.
  • X is a hydrogen atom, or the same or different, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group, C1-C6 anorecoxy C1-C6 alkoxy group, carboxy group, C1-C6 alkoxycarbonyl group, cyano group, force noveramoyl group, N-mono (C1-C6 alkynole) force Rubamoyl group, N, N-di (C1-C6 alkyl) force rubermoyl group, amino group, mono (C1-C6 alkyl) amino group, di (C1-C6 alkyl group) Alkyl) an amino group, a C1-C6 alkylthio
  • X is a hydrogen atom, or the same or different, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a hydroxyl group, a C1-C6 alkoxy group, a halogeno C;! -C6 alkoxy group, 1 to 3 groups selected from the group consisting of a carboxy group, a C1-C6 alkoxycarbonyl group and a cyano group are preferred.
  • Y represents the following formula (a) to (V)
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3v are the same or different and represent a hydrogen atom or a C1-C6 alkyl group
  • R 4a , R 5a , R 4b , R 5b , R 4c , R 5c , R 4d , R 5d , R 4h , R 5h , R 4i , R 5i , R 4j and R 5j are the same or different and are hydrogen atoms , A C1-C6 alkylenole group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkyl group or a C3-C7 cycloalkyl C1-C6 alkyl group, or
  • R 4a and R 5a , R 4b and R 5b , R 4c and R 5c , R 4d and R 5d , R 4h and R 5h , R 4i and R 5i , and R 4j and R 5j are the same or Are different from each other, and are integrated with a nitrogen atom to which two groups are bonded to a 4- to 7-membered nitrogen-containing aliphatic heterocyclic ring (this nitrogen-containing aliphatic heterocyclic ring is a halogeno group, a C1-C6 alkyl group, a halogeno Cl- 1 to 3 groups selected from the group consisting of C6 alkenoquinole group, C1 to C6 alkoxy C1 to C6 alkyl group, hydroxyl group, C1 to C6 alkoxy group, halogeno C1 to C6 alkoxy group and C1 to C6 alkoxy C1 to C6 alkoxy group Each may be substituted.
  • R 4e , R 4f and R 4g are the same or different and are a hydrogen atom, a C1-C6 alkyl group, a halogeno C;! -C6 alkanoleno group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkyl group, C 3 to C 7 cycloalkyl C;! To C 6 alkyl group or phenyl C;!
  • the phenyl group of this phenyl C1 to C6 alkyl group is a halogeno group, a C1 to C6 alkenyl group, a hydroxyl group and C1 1 to 3 groups may be substituted with a group selected from the group consisting of -C6 alkoxy groups).
  • R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10b and R ub are the same or different and represent a hydrogen atom, a halogeno group, a C1-C6 anorequinole group, a halogeno group.
  • R 13l, R 13j, R 13v, R 14c, R 14d, R 14e, R 14f , R 14 ⁇ R 14h , R 14l , R 14j and R 14v are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 alkenoquinole group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 An alkyl group, a hydroxyl group, a C1-C6 alkoxy group, a halogeno C1-C6 alkoxy group or a C1-C6 alkoxy C1-C6 alkoxy group, and k, 1, m, n, o and p are 0, 1 or 2, respectively.
  • Q represents 1 or 2
  • V represents a morpholino group.
  • R 14g , R 14h , R 14i , R 14j , R 14v , k, 1, m, n, o, p and q will be described.
  • R 3a , R 3b , R 3 ⁇ R 3d , R 3 R 3f , R 3g and R 3v are the same or different and are a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group and n-Butyl group is preferred, the same or different, hydrogen atom and methyl group are more preferred! / ,.
  • R 4a, R 5a , R 4b, R 5b, R 4 ⁇ R 5 R 4d, R 5d, R 4h, R 5h, R 4i, R 5i, R 4j and R 5j are the following (1) And (2)
  • R 4a and R 5a , R 4b and R 5b , R 4c and R 5c , R 4d and R 5d , R 4h and R 5h , R 4i and R 5i , and R 4j and R 5j are the same or
  • a 4- to 7-membered nitrogen-containing aliphatic heterocycle integrated with a nitrogen atom to which two groups are bonded is a halogeno group, a C1-C6 alkyl group, a halogeno C1- A group selected from the group consisting of C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group and C1-C6 alkoxy C1-C6 alkoxy group 1-3 May be substituted.) Is preferred
  • R 4a and R 5a , R 4b and R 5b , R 4c and R 5c , R 4d and R 5d , R 4h and R 5h , R 4i and R 5i , and R 4j and R 5j are the same or
  • a pyrrolidine ring or a piperidine ring combined with a nitrogen atom to which two groups are bonded are a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group and C1-C6 alkoxy group selected from the group consisting of C1-C6 alkoxy group 1-3 Is more preferred.
  • R 4e , R 4f and R 4g are the same or different and each represents a hydrogen atom, a C1-C4 alkyl group, a halogeno C1-C4 alkyl group, a C1-C4 alkoxy C1-C4 alkyl group, a C3-C5 cycloanol. Kill group, C3-C5 cycloalkyl C1-C4 alkyl group and phenyl C;!
  • the phenyl group of this phenyl C1-C4 alkyl group is a halogeno group, C1-C4 alkyl group, hydroxyl group and 1 to 3 groups may be substituted with a group selected from the group consisting of C1 to C4 alkoxy groups).
  • R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10b, and R ub are the same or different and represent a hydrogen atom, a halogeno group, or a C1-C4 anolenoquine group
  • a halogeno C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 alkyl group, a hydroxyl group, a C1-C4 alkoxy group, a halogeno C1-C4 alkoxy group, and a C1-C4 alkoxy C1-C4 alkoxy group are preferred.
  • R 13h, R 13l, R 13j , R 13v, R 14c, R 14d, R 14e, R 14f, R 14g, R 14h, R 14l, R 14j and R 14v are the same or different and each represents a hydrogen atom, a halogeno Groups, C1-C4 alkanoleno groups, halogeno C1-C4 alkynole groups, C1-C4 alkoxy C1-C4 alkyl groups, hydroxyl groups, C1-C4 alkoxy groups, halogeno C1-C4 alkoxy groups and C1-C4 alkoxy C1-C4 alkoxy groups Is preferred.
  • k, 1, m, n, o and p are each preferably 0 or 1, more preferably 0. q is preferably 1.
  • R 2 is preferably a C1-C6 alkyl group and a C3-C7 cycloalkyl group which may have a substituent.
  • Examples of the optionally substituted C1-C6 alkyl group include C1-C6 anolenoquinole group, and the following halogeno group, C3-C7 cycloalkyl group, phenyl group (this phenyl group is a halogeno group, C1 1 to 3 groups may be substituted with a group selected from the group consisting of ⁇ C6 anolenoquinole group, hydroxyl group and C1 to C6 alkoxy group), 5- or 6-membered aromatic heterocyclic group (this aromatic heterocyclic group) 1 to 3 of the aromatic heterocycles may be substituted with a group selected from the group consisting of a no, a logeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group.
  • the aliphatic heterocyclic ring of this aliphatic heterocyclic group is a group selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group.
  • 4 to 7-membered aliphatic heterocyclic group CO group (this aliphatic group may be substituted)
  • Heterocyclic group, a halogeno group, C1 -C6 alkyl group, a hydroxyl group and C1 -C6 alkoxy 1 to 3 groups may be substituted with a group selected from the group consisting of xy groups.
  • a benzylamino group (the benzyl group of the benzylamino group may be selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group). 1 to 3 groups may be substituted.), C;!
  • C1 to C6 alkylsulfinyl group C1 to C6 alkylsulfonyl group, phenylthio group (the phenylthio group)
  • the phenyl group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkenyl group, a hydroxyl group and a C1-C6 alkoxy group), a phenylsulfinyl group (this phenyl group).
  • the phenyl group of the sulfinyl group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group.), And phenyls A sulfonyl group (the phenyl group of this phenylsulfonyl group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group).
  • R 2 is a C1 to C6 alkylenole group, a halogeno C1 to C6 alkyl group, a C3 to C7 cycloalkyl C1 to C6 alkyl group, a phenyl C;! To C6 alkyl group (this phenyl C;! To C6 alkyl)
  • the phenyl group of the group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkenyl group, a hydroxyl group, and a C1-C6 alkoxy group.
  • Aromatic heterocyclic group C1-C6 alkyl group (The aromatic heterocyclic ring of this aromatic heterocyclic group is selected from the group consisting of a group consisting of a no, a logeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group. It may be substituted with 1 to 3 groups.
  • a 4- to 7-membered aliphatic heterocyclic group C1-C6 alkyl group (the aliphatic heterocyclic ring of this aliphatic heterocyclic group comprises a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group) 1 to 3 groups may be substituted with a group selected from the group), a 4- to 7-membered aliphatic heterocyclic group CO—C1-C6 alkyl group (this aliphatic heterocyclic group is a halogeno group, 1 to 3 groups may be substituted with a group selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group.), A hydroxy C1-C6 alkanoleno group, a C1-C6 alkoxy C1-C6 An alkyl group, a phenoxy C1-C6 alkyl
  • R 2 is a C1 to C6 alkylenole group, a halogeno C1 to C6 alkyl group, a C3 to C7 cycloalkylene C1 to C6 alkyl group, a phenyl C;! To C6 alkyl group (this phenyl C;!
  • the phenyl group in the group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkenoquinole group, a hydroxyl group, and a C1-C6 alkoxy group.),
  • a 4- to 7-membered fat Aromatic heterocyclic group CO—C1-C6 alkyl group (This aliphatic heterocyclic group is substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group.
  • R 2 includes C1-C6 anolenoquinole group, fluoro C1-C6 alkyl group, C3-C7 cycloalkylmethyl group, benzyl group (this benzyl group is a halogeno group, C1-C6 alkyl group, hydroxyl group and C1- 1 to 3 groups may be substituted with a group selected from the group consisting of C6 alkoxy groups.) Examples include methylthio C1-C6 alkyl groups and C3-C7 cycloalkyl groups.
  • R 2 includes methyl group, ethyl group, n propyl group, isopropinole group, n butyl group, isobutyl group, tert butyl group, n pentyl group, 3-methyl-n butyl group, n heptyl group, 4 -Methyl-n-pentyl group, 3-fluoro-n-pro Pinole group, 4-fluoro-n-butyl group, 4-fluoro-3-methyl-n-butyl group, 5-fluoro-n-pentyl group, 6-fluoro-n-hexyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclo A hexylmethyl group, a benzyl group (this benzyl group may be substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1 to C6 alkenyl group, a
  • R 2 includes 3-fluoro-n-propyl, 4-fluoro-n-butyl, 4-fluoro-3-methyl-n-butyl, 5-fluoro-n-pentynol, 6-fluoro-n-hexyl, cyclopropylmethyl Group, cyclobutylmethyl group, cyclopentylmethyl group, benzyl group (this benzyl group is substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkylene group, a hydroxyl group and a C1-C6 alkoxy group) And a methylthioethyl group, a methylthiopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
  • R 1 in the general formula (I) is more preferably a hydrogen atom, preferably a hydrogen atom, a methyl group or an ethyl group.
  • Ring A in general formula (I) is preferably a benzene ring, furan ring, thiophene ring, pyrrole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring.
  • Particularly preferred is a 1,4-phenylene group where the benzene ring is more preferred.
  • X in the general formula (I) is a hydrogen atom, or the same or different, a halogeno group, C1
  • a group having 1 to 3 groups selected from the group consisting of a -C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group is preferred.
  • the compound of the general formula (I) has the following general formula (I a) wherein R 1 is a hydrogen atom; and ring A is a 1,4-phenylene group;
  • Y in the general formula (I) is a group represented by the above formula (a), (c), (e), (f), (h), (i) or (v).
  • a group represented by the formula (a), (e) or (v) is more preferable.
  • R 3y and ⁇ are the same or different and each represents a hydrogen atom or a C1-C6 alkyl group
  • R 4y and R 5y are the same or different and are a hydrogen atom, C1-C6 anolenoquinole group, halogeno C;! -C6 alkenoquinole group, C1-C6 alkoxy C1-C6 alkyl group, C3-C7 cycloalkyl group or C3- C 7 cycloalkyl C;! To C 6 alkyl group,
  • R 6y , R 6z , R 7y , R 7z , R 8y , R 8z , R 9y and R 9z are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 anorequinole group, a halogeno C1-C6 alkyl group, C1-C6 alkoxy C;! -C6 alkenoquinole group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy C1-C6 alkoxy group,
  • R 15z , R 16z and R 17z are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a hydroxyl group, C1 -C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy C1-C6 alkoxy group is shown. ) Is more preferable.
  • the compound of the general formula (I) has the following general formula (I b) wherein Y is the formula (y) and (z) above; R 1 is a hydrogen atom; and the ring A is a 1,4-phenylene group. ) And (I c)
  • a compound represented by the formula: salt thereof or solvate thereof is more preferred!
  • R 3y and R 3z in the formulas (y) and (z) are the same or different and are preferably a hydrogen atom and a methyl group.
  • R 6y , R 6z , R 7y , R 7z , R 8y , R 8z , R 9y and R 9z are the same or different and represent a hydrogen atom and C1 to C6. Alkyl groups are preferred.
  • Y is preferably a group represented by the formula (z)! /.
  • R 15z , R 16z and R 17z in the formula (z) are the same or different and are preferably a hydrogen atom, a halogeno group, a C1-C6 anolenoquinole group, a halogeno C1-C6 alkyl group or a C1-C6 alkoxy group. Good.
  • R 3e in formula (e) is preferably a hydrogen atom
  • R 4e is preferably a hydrogen atom
  • R 12e R 13e and R 14e are the same or different, and a hydrogen atom, a halogeno group, or a C1-C6 alkoxy group is preferred, and o is preferably 0.
  • R 3v in formula (V) is preferably a hydrogen atom
  • R 12e , R 13e and R 14e are the same or Differently, a hydrogen atom or a C1-C6 alkyl group is preferred.
  • Q is preferably 1.
  • V is preferably a 3-morpholinyl group or a 4-morpholinyl group.
  • more preferable compounds among the compounds of the general formula (I) are those described in Examples 46, 47, 48, 51, 52, 53, 54, 55, 56, 60, 61, 67, 69 or 71. Or a salt thereof or a solvate thereof.
  • Preferred is one selected from the group consisting of: one compound, a salt thereof, or a solvate thereof.
  • a force any force selected from the group, one compound, a salt thereof or a solvate thereof is also preferred.
  • salts include, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfate, phosphate Inorganic acid salts such as methane sulfonate, trifluoro methane sulfonate, lower alkane sulfonate such as ethane sulfonate, benzene sulfonate, p Aryl sulfonate such as toluene sulfonate, acetic acid, apple Organic acids such as acid, fumarate, succinate, succinate, tartrate, succinate, maleate And amino acid salts such as ornithate, glutamate, and aspartate; hydrohalides and organic acid salts are preferred.
  • hydrohalides and organic acid salts are preferred.
  • the compound of the present invention represented by the general formula (I) has an acidic group such as a carboxy group, it is generally possible to form a base addition salt.
  • pharmaceutically acceptable salts include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; dibenzylamine salt and morpholine.
  • Salt phenylglycine alkyl ester salt, ethylene diamine salt, N-methyl darcamamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt , Diethanolamine salts, N-benzyl-N- (2-phenylethoxy) amine salts, piperazine salts, tetramethylammonium salts, organic amine salts such as tris (hydroxymethyl) aminomethane salts; Power S can be.
  • the compound represented by the general formula (I) of the present invention or a salt thereof may exist as a free form or a solvate.
  • the solvate is not particularly limited as long as it is pharmaceutically acceptable, and specifically, a hydrate, an ethanolate, and the like are preferable.
  • a nitrogen atom when present in the compound of the present invention represented by the general formula (I), it may be an N-oxide and may be V, and these solvates and N-oxides are also present in the present invention. Included in the range.
  • the compound of the present invention represented by the general formula (I), a salt thereof, or a solvate thereof may be a geometric isomer such as a cis isomer or a trans isomer, a tautomer, There may be various isomers such as optical isomers such as d-form, 1-form, etc., but the compounds of the present invention are particularly limited! /, NA! /, in some cases, all isomers, stereoisomers and Also included are isomers and stereoisomer mixtures in the ratio of deviation and deviation.
  • the present invention also relates to a compound that is converted into compound (I) that is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, enzymatically.
  • a “pharmaceutically acceptable prodrug compound” that is converted to compound (I) by oxidation, reduction, hydrolysis, etc., or is converted to compound (I) by hydrolysis or the like by gastric acid or the like. It is included in the present invention.
  • the prodrug when an amino group is present in the compound (I), a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosano Silylation, araelation, pentylaminocarbonylation, (5 methinoyl-2-oxo1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethinolation, bivalyloxymethylation, tert
  • the compound (I) has a hydroxyl group
  • the compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (such as a butylated compound).
  • a compound in which the hydroxyl group is acetylated, normitinoylated, propanoylated, bivalylated, succinylated, fumarylated, araerylated, dimethylaminomethylcarbonylated, etc.
  • a carboxy group is present in the compound (I)
  • a compound in which the carboxy group is esterified or amidated for example, the carboxy group is ethyl esterified, phenol esterified, carboxymethyl esterified, Dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxetyl esterification, amidation, or methylamidation compound).
  • a prodrug of the compound of the present invention can be produced from compound (I) by a known method.
  • the prodrug of the compound of the present invention changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. Also included.
  • the compound represented by the general formula (I) and production intermediates thereof can be produced by utilizing various known reactions described below.
  • the functional group may be protected with an appropriate protecting group at the raw material or intermediate stage.
  • Examples of such functional groups include a hydroxyl group, a force carboxy group, an amino group, and the like.
  • the types of protecting groups and the conditions for introducing and removing these protecting groups are, for example, Protective Groups in Organic Synthesis (T W. Green and PGM Wuts, John Wiley & Sons, Inc., New York, 1991).
  • Compound (I) of the present invention can be produced by the following [Production Method 1].
  • Compound (I) of the present invention is produced by producing compound (3) by nucleophilic substitution reaction between compound (1) and amine (2), and compound (4) which is a carboxylic acid derivative from compound (3). Can be produced by condensing the compound (4) with the amine (5).
  • Compound (3) is obtained by treating compound (1) with a stoichiometric amine (2) in the presence of a base. It can be produced by a nuclear substitution reaction. In this reaction, an excess amount of ammine (2) may be used as a base.
  • the amine (2) may be commercially available or produced by a known method.
  • the compound (3) can be obtained by reacting the compound (1) with a commercially available amine and then leading to the desired R 1 and / or R 2 using a known method. For example, when synthesizing (3) having a fluoroalkyl group at R 2 , after reacting hydroxyalkylamine with (1), the newly introduced nitrogen atom of the obtained compound is appropriately substituted.
  • a leaving group such as a methanesulfonyl group
  • tetraptyl ammonium fluoride examples include organic amine bases such as triethylamine and diisopropylethylamine.
  • the amount of base used is preferably 2 to 10 times the molar equivalent of compound (1)! /.
  • the amount of amine (2) to be used is: when using a base;! ⁇ 2 molar equivalents should not be used with a base; in this case, the range of 2-30 molar equivalents relative to compound (1) I like it!
  • the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • amide solvents such as N methyl-2-pyridone
  • dimethyl examples include sulfoxide solvents such as sulfoxide (DMSO), and DMF, DMSO and the like are preferable.
  • the reaction temperature is preferably in the range of 80 to 160 ° C.
  • the reaction time is usually about 1 to 24 hours.
  • R ⁇ and R b are the same or different and represent a hydrogen atom or a C1 to C6 alkyl group, or R 2 ° a and R 2 ° b form a C1 ⁇ R 21 represents a carboxy group, a formyl group, or a C1-C6 alkoxycarbonyl group, and a ring A, R 2 and X are the same as described above.
  • Compound (4) which is a carboxylic acid derivative, is produced by coupling compound (3) and organic boronic acid derivative (6) to produce compound (4a).
  • Compound (4a) is converted to (1) R When 21 is a formyl group, it is oxidized, and when (2) R 21 is a C1-C6 alkoxycarbonyl group, the angle of hydrolysis is increased and the production force S is reduced.
  • Compound (4a) is obtained by converting compound (3) into an organic boronic acid derivative in the presence of a metal catalyst and a base.
  • the organic boronic acid derivative (6) is commercially available or can be produced by a known method. References for the production method and the coupling reaction of the organic boronic acid derivative (6) include “Chemical Reviews, 1995, 95, 2457-2483”. I ’ll give you the power S.
  • the amount of the organic boronic acid derivative (6) used is preferably in the range of 1 to 2 molar equivalents of the compound (3).
  • Palladium catalysts are preferred as metal catalysts.
  • metal catalysts For example, [1, bis (diphenylphosphino) phenocene] dichloropalladium (II) / dichloromethane complex (1: 1) or dichlorobis (triphenylphosphine) palladium (II). And tetrakis (triphenylphosphine) paradium (0).
  • the amount of the metal catalyst used is preferably in the range of 0.01-0.2 molar equivalents relative to compound (3).
  • the base examples include inorganic bases such as tripotassium phosphate (hydrate), potassium carbonate, cesium carbonate, etc. Tripotassium phosphate (hydrate) and potassium carbonate are preferred.
  • the amount of the base used is preferably in the range of 0.2 to 10-fold molar equivalent to the compound (3).
  • the additive examples include organic phosphorus compounds such as 1,1,1 bis (diphenylphosphino) phenocene (dppf), triphenylphosphine, and the amount of the additive used is compound (3).
  • organic phosphorus compounds such as 1,1,1 bis (diphenylphosphino) phenocene (dppf), triphenylphosphine, and the amount of the additive used is compound (3).
  • the range of 0.05-0.2 molar equivalent is preferred.
  • the solvent for the coupling reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent.
  • ether solvents such as 1,4 dioxane and 1,2-dimethoxyethane
  • N, N Amide solvents such as dimethylformamide (DMF) and N-methyl-2-pyrrolidone
  • hydrocarbon solvents such as toluene and benzene
  • alcohol solvents such as methanol and ethanol
  • polar solvents such as acetonitrile and water are preferred.
  • solvents may be used as a mixed solvent of two or more.
  • the reaction temperature is in the range of 50 ° C to the boiling point of the solvent, preferably in the range of 70 to 150 ° C.
  • the reaction time is usually about 1 to 50 hours.
  • Compound (4) can be produced by oxidizing compound (4a), which is an aldehyde derivative.
  • R 21 is a C1-C6 alkoxycarbonyl group
  • the compound (4) can be obtained by the ability S to produce the compound (4a) which is a C1-C6 alkyl ester derivative by hydrolysis reaction.
  • Compound (I) can be produced by condensing compound (4) with amine compound (5) in the presence of a condensing agent. This condensation reaction may be performed in the presence of a base and / or an additive in order to accelerate the reaction.
  • the amine body (5) is commercially available or can be produced by the method described below.
  • the amount of the amine compound (5) used is preferably in the range of 0.6 to 4.0 times molar equivalent to the compound (4).
  • condensing agent examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), benzotriazole-1yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O benzotriazole 1—yl N, N, ⁇ ', ⁇ , 1 tetramethyluronium hexafluorophosphate, 4— (4, 6-dimethoxy-1, 3,4,5-triazine-2-yl ) -4-Methylmorpholinum chloride and the like, etc.
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • BOP benzotriazole-1yloxytris (dimethylamino) phosphonium hexafluorophosphate
  • EDC 1-Ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • benzotriazole-1-iloxytris Dimethylamino) phosphonium hexafluorophosphate ( ⁇ )
  • the amount of the condensing agent used is preferably in the range of 0.8 to 3 molar equivalents relative to compound (4).
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • amide solvents such as ⁇ , ⁇ ⁇ ⁇ ⁇ dimethylformamide, ⁇ methyl-2-pyrrolidone, dichloromethane, black mouth form, etc.
  • Halogenated hydrocarbon solvent These solvents, which are preferably ether solvents such as tilether and tetrahydrofuran, and hydrocarbon solvents such as toluene and benzene, may be used as a mixed solvent of two or more.
  • the additive examples include 1-hydroxybenzotriazole (HOBt).
  • HOBt 1-hydroxybenzotriazole
  • the amount used is preferably in the range of 0.;! To 1-fold molar equivalent to the compound (4).
  • the base include organic amine bases such as triethylamine and diisopropylethylamine.
  • the amount used is preferably in the range of 1 to 8 molar equivalents relative to compound (4)! /.
  • the reaction temperature is preferably in the range of 0 ° C to the boiling point of the solvent! /.
  • the reaction time is usually about 1 hour to 4 days.
  • the functional group such as an amino group When a functional group such as an amino group is present on the group Y of the compound (I) obtained by this production method, the functional group such as the amino group may be protected. A generally used method such as the above may be used. Further, the amino group can be converted to a substituted amino group by alkylation or the like by a general method.
  • the compound (I) of the present invention can be produced by [Route A] or [Route B] shown in [Production Method 2] below with the force S.
  • the compound of the general formula (I) is produced from the compound (1) and the organic boronic acid derivative (6) by the coupling reaction shown in [Production method 12], and from the compound (7a) [ Compound (7b), which is a carboxylic acid derivative, is produced by the method shown in Production method 12], and compound (8b) is produced from compound (7b) and amine compound (5) by the condensation reaction shown in [Production method 13]. ), And can be produced from compound (8) and amine (2) by applying the nucleophilic substitution reaction shown in [Production Method 1 1].
  • the compound of the general formula (I) is produced from the compound (4) by the nucleophilic substitution reaction between the carboxylic acid derivative compound (7b) and the amine (2). It can be produced by a condensation reaction with the amine body (5) shown in 3].
  • the functional group such as an amino group when present on the group Y of the compound (8) or the compound (I), the functional group such as the amino group may be protected.
  • a generally used method may be used as described above.
  • the amino group can be converted to a substituted amino group by alkylation or the like by a general method.
  • the amine compound (5) is represented by the following formula (5-a):
  • a ia represents a methylene group or an ethylene group (the methylene group and the ethylene group are the same or different and are each a halogeno group, a C1-C6 anolenoquinol group, a halogeno C1-C6 alkyl group, C;!- C6-alkoxy C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C;! -C6 alkoxy group and C1-C6 alkoxy group are substituted with 1 to 4 groups selected from the group consisting of C1-C6 alkoxy groups R 3a , R 4a and R 5a are the same as described above. Can be produced by the following [Production Method A-1].
  • Amin (5-a) produces compound (10) by a reductive amination reaction in which aldehyde (9) and ammine (9a) or a salt thereof are treated in the presence of a reducing agent. Next, it is possible to manufacture by deprotecting compound (10).
  • the aldehyde (9) and the amine body (9a) or a salt thereof used for the reductive amination reaction are commercially available or can be produced by a known method.
  • As a reference for the reductive amination reaction there is an experimental chemistry course (4th edition, Vol. 20, edited by Japan Chemical Society, Maruzen Co., Ltd.) "Organic Synthesis II: Alcohol 'Amin, P300-P302". Touch with force S.
  • the amount of the amine compound (9a) or salt thereof used is preferably in the range of 0.;! To 4 times molar equivalents relative to the compound (9).
  • metal hydrides are preferred, for example, sodium borohydride, Sodium borohydride, sodium triacetoxyborohydride and the like are preferable.
  • the amount of the reducing agent used is preferably in the range of 0.2 to 4 molar equivalents relative to compound (9).
  • the reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, etc., chloroform, dichloromethane, 1, Halogenated hydrocarbon solvents such as 2-dichloroethane, jetyl ether, tetrahydrofuran, 1 ; ether solvents such as 4-dioxane, alcohol solvents such as methanol and ethanol, N, N-dimethylformamide, N-methyl-2-pyrrolidone
  • amide solvents, sulfoxide solvents such as dimethyl sulfoxide, polar solvents such as acetonitrile, water, and acetic acid are preferred. These solvents may be used as a mixture of two or more.
  • the reaction temperature is in the range of 0 ° C to the boiling point of the solvent, preferably in the range of 20 ° C to 80 ° C.
  • the reaction time is usually about 1 hour to 3 days.
  • the amine compound (5) is represented by the following formula (5-b):
  • ring B represents a cyclopentane ring or a cyclohexane ring
  • R 4e,! T e , R 12e , R 13e , R 14e , k, and 1 represent the same as described above.
  • Amine (5-b) is a compound (12) produced by protecting one amino group of diamine body (11), and compound (12) is alkylated in the presence of a commonly used base.
  • the compound (13) is produced by applying the alkylation reaction treated with an agent, or applying the reductive amination reaction of [Production method A-1], and deprotecting the compound (13). can do.
  • References for the alkylation reaction and reductive amination reaction include the Experimental Chemistry Course (4th Edition, Vol. 20. The Chemical Society of Japan, Maruzen Co., Ltd.) “Organic Synthesis II: Alcohol. ⁇ P302 "etc. Power S
  • the above-mentioned diamine (11) is commercially available or can be produced by a known method.
  • Bases used for alkylation include organic amine bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, or inorganic bases such as potassium carbonate and cesium carbonate. preferable.
  • the amount of the base used can be in the range of 1 to 30 equivalents, preferably in the range of !! to 10 equivalents, relative to the compound (12).
  • the reaction time is usually about 1 to 48 hours.
  • the leaving group (U includes, for example, a neurogeno group, a C1-C6 alkylsulfonyloxy group, a phenylsulfonyloxy group which may have a substituent, and the like.
  • Elementary atoms, methanesulfonyloxy groups, benzenesulfonyloxy groups and p-toluenesulfonyloxy groups are preferred.
  • the reaction solvent for alkylation is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
  • Halogenated hydrocarbon solvents such as chloroform and dichloromethane, and hydrocarbons such as toluene and benzene.
  • Solvents such as organic solvents, ether solvents such as jetyl ether and tetrahydrofuran, alcohol solvents such as methanol and ethanol, amide solvents such as N and N dimethylformamide, polar solvents such as acetonitrile and water are preferred. You may use a solvent as a 2 or more types of mixed solvent.
  • the reaction temperature is in the range of 20 ° C to the boiling point of the solvent, preferably in the range of room temperature to 80 ° C.
  • the reaction time is usually about 1 to 48 hours.
  • the amine compound (5) is represented by the following formula (5-c 1):
  • R 3g , R 4g , R 12g , R 1 and R 14g represent the same as described above.
  • PG 1 and PG 2 represent protecting groups, and r, R, R 4 ⁇ R 1 , R 1 and R 14g represent the same as described above.
  • Amine (5-c 1) is produced by protecting compound (14), which is commercially available or can be produced by a known method, to produce compound (15), and selectively deprotecting compound (15)
  • Compound (16) can be produced by the reaction, compound (16) can be produced by alkylation reaction or reductive amination reaction, compound (17) can be produced, and compound (17) can be deprotected.
  • References for alkylation reactions and reductive amination reactions include the Experimental Chemistry Course (4th edition, Vol. 20. Edited by the Chemical Society of Japan, Maruzen Co., Ltd.) “Organic Synthesis II: Alcohol 'Amin, P284-P288 and P300. ⁇ P 302 "etc. Power S
  • the amine compound (5) is represented by the following formula (5-c 2)
  • R 1 represents a hydrogen atom, a C1-C6 anolenoquinole group, an optionally substituted phenyl group or an optionally substituted benzyl group
  • R 23 represents a methyl group.
  • a group, a halogenomethyl group, having a substituent may be! /, Having a phenyl group or a substituent! /, May! /,
  • a benzyl group, R 4e , R 12e , R 13e , R 14e and o are the same as above.
  • Amine (5-c-2) is prepared by reducing compound (18) to produce alcohol (19), and sulfonylating alcohol (19) to produce compound (20). ) Can be produced by azidating to produce compound (21) and reducing compound (21).
  • the amine compound (5) is represented by the following formula (5-d-1) or (5-d-2):
  • Amine (5-dl or 5-dl-2) is an aldehyde (22a) or ketone (22b)
  • the amine body (5) is represented by the following formula (5-e-1)
  • Amin (5-e- 1) was synthesized by a known method
  • Carboxylic acid ester (25) having a morpholine ring can be synthesized by the same operation as the synthesis route described in Production method A-4.
  • the compound (I) of the present invention produced by the above method can be isolated and purified by a known method such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like. . Further, when the compound (I) of the present invention or the intermediate of production has an asymmetric carbon, an optical isomer exists.
  • optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) recrystallizing with an appropriate salt and column chromatography.
  • fractional recrystallization salt resolution
  • TNF-a production inhibitors are useful as therapeutic agents for various inflammatory diseases such as rheumatoid arthritis or autoimmune diseases.
  • inflammatory diseases include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritability To mention genital bowel syndrome, mucinous colitis, ulcerative colitis, Crohn's disease, multiple sclerosis, etc.
  • autoimmune diseases include collagen disease, systemic lupus erythematosus, rheumatoid arthritis, spondylitis, osteoarthritis, ventilation, sepsis, septic shock, toxic shock syndrome, and atopic skin.
  • Inflammation contact dermatitis, multiple sclerosis, Behcet's disease, nephew syndrome, lupus nephritis, glomerulonephritis, Syudalen syndrome, lupus erythematosus, force hex, scleroderma, polymyositis, psoriasis, inflammation Enteric disease, Crohn's disease, mixed connective tissue disease, chronic obstructive pulmonary disease, retention cardiac arrest, pulmonary fibrosis, primary myxedema, Addison's disease, aplastic anemia, autoimmune hemolytic anemia, autoimmunity Thrombocytopenia, autoimmune diabetes, insulin resistance, uveitis, antireceptor disease, myasthenia gravis, thyroid poisoning, thyroiditis, Hashimoto's disease, viral infection, AIDS, etc.
  • the medicament of the present invention can be produced by selecting an appropriate form according to the administration method and preparing various preparations usually used.
  • Examples of the pharmaceutical form for oral use include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like.
  • the preparation of these forms of pharmaceuticals consists of excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives.
  • an oxidizing agent a coloring agent, a solubilizing agent, a suspending agent, an emulsifier, a sweetener, a preservative, a buffering agent, a diluent, a wetting agent, etc. Can do.
  • compositions for parenteral use include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, And inhalants.
  • the preparation of these forms of pharmaceuticals includes stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives.
  • Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
  • the medicament of the present invention comprises a compound represented by the general formula (I), a salt thereof or a solvate thereof, an immunosuppressant, an antibody used for immunosuppression, a therapeutic agent for rejection, an antibiotic, a nonsteroid It may be a pharmaceutical comprising one or more selected from sex anti-inflammatory drugs (NSAIDs) and steroid drugs.
  • This medicament is administered as a combination drug by combining the compound of the present invention represented by the general formula (I), a salt thereof or a solvate thereof and one or more of other drugs.
  • the combination of the compound of the present invention represented by the general formula (I), a salt thereof or a solvate thereof and another drug is a combination of both components in one preparation.
  • each preparation may be administered as a separate formulation.
  • each preparation may be administered at the same time or at a time difference.
  • the administration method of each preparation may be the same or different.
  • These medicines include compounds represented by general formula (I), salts thereof or solvates thereof, immunosuppressants, antibodies used for immunosuppression, rejection drugs, antibiotics, nonsteroidal anti-inflammatory drugs. It may be a kit that combines (NSAIDs) and other drugs such as one or more selected from steroid drugs.
  • an antibody used for immunosuppression and a rejection treatment
  • cyclosporine 8 tacrolimus (FK506), sirolimus (rapamycin), azathioprine, mizoribine, methotrexate, mycophenolate mofuethyl, cyclophosphamide, sirolimus, everolimus, prednisolone, methinoreprednisolone, onoleclone OKT globulin , Deoxyspargarine, etanercebut, infliximab or rituxan.
  • Antibiotics include, for example, cefuroxime sodium, meropenem trihydrate, netilmycin sulfate, sisomycin, ceftibutene, ⁇ -1806, IB-367, tobramycin, PA-1420, doxorubicin, astrol sulfate Mycin, ceftametopivoxil hydrochloride, and the like.
  • Non-steroidal anti-inflammatory drugs include, for example, aspirin, salicylic acid, diclofenac, indomethacin, ibuprofen, ketoprofen, loxoprofen, naproxen, piroxicam, meloximac, aceclofenac, actarito, dicereine, Etc.
  • Examples of steroid drugs include clobetasol propionate, diflorazone acetate, fluoconide, mometasone furanate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, budesonide, diph Lucortron, amsinonide, harsinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydroconorethione butyrate, hydrocortisone butyrate propionate, deprodon propionate, prednisolone acetic acid prednisolone, fluosinolone Beclomethasone, triamcinolone acetonide, flumethasone pivalate, alcromethasone propionate, clobetasone butyrate, predoni Ron
  • the dose of the compound of the present invention represented by the general formula (I), a salt thereof, or a solvate thereof varies depending on symptoms, age, body weight, type of drug administered in combination, dose, etc.
  • amount of Compound (I) per adult from 0.OOlmg to! OOOmg, systemically or locally, administered once or several times a day, orally or parenterally, Or it is preferably administered intravenously in the range of 1 to 24 hours per day.
  • the pharmaceutical containing the compound of the present invention is preferably administered as a compound once a day for an adult and repeated at appropriate intervals.
  • the dosage is in the range of 0.01 mg to 2000 mg, preferably ⁇ 0.1 mg to;! OOOmg in the range, more preferably ⁇ mg to 500 mg.
  • the medicament of the present invention is used in combination with rheumatoid arthritis drugs, anti-psoriatic drugs, bronchodilators, anti-bronchial asthma drugs or antidiabetic drugs, as long as the effects of the present invention are not impaired. Can be used.
  • the present invention also includes a method for preventing and / or treating the aforementioned disease, which comprises administering the compound of the present invention or a salt thereof.
  • the present invention also includes use of the compound of the present invention, a salt thereof, or a solvate thereof for producing the aforementioned medicament.
  • Infrared spectrum was measured by KBr tableting method or ATR method using Hitachi 270-30 spectrometer or Horiba FT-720 (ST Japan Durascope (Diamond / KRS-5)). Analysis was performed with Perkin—Elmer CHNS / O 2400 (II), MITS UBISHI CHEMICAL XS—100, or DIONEX DX—320, and mass (MS) analysis was performed using JEOL JMS-AX505W (EI, FAB, CI).
  • the silica gel used for column chromatography was Kiesel-gel 60 (particle size 0.060-0.200 mm) from E-Merck.
  • Kieselgel 60 F manufactured by E-Merck was used.
  • the reaction solution was concentrated under reduced pressure until it was about half volume.
  • the produced precipitate was collected by suction filtration and washed with 1,2-dimethoxyethane and ether to obtain a crystalline powder.
  • the obtained crystalline powder was added to a saturated aqueous sodium hydrogen carbonate solution (1200 ml) and stirred vigorously until the foaming subsided.
  • the precipitate was collected by filtration under reduced pressure, and washed with a saturated aqueous sodium bicarbonate solution and water.
  • the obtained solid was dried under reduced pressure to obtain the title compound (94. Og, 74%).
  • the obtained crystalline powder was dissolved in dichloromethane (1000 ml) and washed with 1N aqueous sodium hydroxide solution (1000 ml). The dichloromethane layer was separated and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was suspended in a hexane / ethyl acetate mixture (10: 1) and collected by filtration under reduced pressure to obtain the title compound (102.8 g, 92%).
  • Step 2 4- [6-[(3,4-Dichlorodiethyl) amino] imidazo [1,2-b] pyridazine 3-yl] benzoic acid ethyl ester
  • Step 4 4- [6-[(3,4-Dichlorodiethyl) amino] imidazo [1,2-b] pyridazine 3-yl] N— [2 (dimethylamino) ethyl] benzamide hydrochloride
  • the obtained solid was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure.
  • the concentrated residue was dissolved in methanol, 1N hydrochloric acid (ethanol solution) was added, and the mixture was concentrated under reduced pressure. Methanol was added to the concentrated residue and vacuum concentration was repeated several times.
  • Dichloromethane was added to the concentrated residue, and the solid was collected by filtration and washed with hexane.
  • the obtained powdery substance was dried under reduced pressure at 80 ° C. to obtain the title compound (26 mg, 19%).
  • IR (ATR) cm _1 3248, 3053, 2679, 1610, 1508, 1492, 1469, 1331, 1292
  • Step 2 4- [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] benzoic acid
  • Step 3 4- [6 -— [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] N— [2- (tert-butoxycarbonylamino) ethyl] benzamide [0214] 51]
  • Step 4 [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] N— (2-aminoethyl) benzamide trifluoroacetate
  • the product was purified by HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. 1N Hydrochloric acid (ethanol solution) was added to the concentrated residue, and the mixture was concentrated under reduced pressure to obtain the title compound (186 mg, 45%).
  • reaction mixture was concentrated under reduced pressure, and the concentrated residue was subjected to preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase : Acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. 1N hydrochloric acid (ethanol solution) was added to the residue, and the mixture was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate and dried under reduced pressure at 90 ° C. for 3 days to obtain the title compound (157 mg, 68%).
  • IR (ATR) cm _1 3253, 3049, 2578, 2474, 1624, 1537, 1502, 1466, 1406, 1348, 1281, 1238, 1080, 1016, 831, 764, 667, 586, 476.
  • the target fraction was made basic by adding sodium hydrogen carbonate, and extracted with a dichloromethane / methanol mixture. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Dichloromethane / hexane mixture was added to the residue, and the solid was filtered to obtain the title compound (67 mg, 30%).
  • Step 1 ( ⁇ ) — [(1R, 2R) — 2- (Dimethylamino) cyclopentyl] strength rubamic acid t ert pino estole
  • the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the obtained residue was purified by preparative HPLC (column: NOMURA Development Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fractions were collected.
  • the target fraction was made basic by adding sodium bicarbonate and extracted with a dichloromethane / methanolate mixture.
  • the obtained extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added a dichloromethane / hexane mixture, and the solid was collected by filtration to obtain the title compound (47 mg, 20%).
  • the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure.
  • the reaction mixture was concentrated under reduced pressure, and black mouthform was added to the concentrated residue.
  • the black mouth form solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate.
  • the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
  • the concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid).
  • the target fraction was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the resulting concentrated solution to make it liquid and then extracted with black mouth form.
  • the black mouth form layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the concentrated residue was dissolved in a small amount of ethyl acetate and added dropwise to hexane while applying ultrasonic waves. The resulting precipitate was collected by filtration to give the title compound (85 mg, 54%).
  • IR (ATR) cm_1 3299, 2962, 2798, 1606, 1577, 1490, 1425, 1332, 1286, 1168, 954, 833, 811, 765.
  • Step 2 2-methyl-4- (4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolane 2-yl) benzoic acid methyl ester
  • Step 4 4- [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] 2-methylbenzoic acid [0248] [Chemical 68]
  • Step 5 4- [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] N- [2- (dimethylamino) ethyl] 2-methylbenzamide dihydrochloride
  • Step 2 [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] 3-methylbenzoic acid methyl ester
  • the concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. 1N Hydrochloric acid (ethanol solution) was added to the concentrated residue, and the mixture was concentrated under reduced pressure to obtain the title compound (133 mg, 84%).
  • Step 1 5- [6 — [(Cyclopropylmethyl) amino] imidazo [1, 2-b] pyridazine-3 Il] thiophene 2—power rubonic acid
  • Step 2 [6 -— [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] N— [2- (dimethylamino) ethyl] thiophene 2-carboxamide dihydrochloride
  • the concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile, water / formic acid), and the target fraction was concentrated under reduced pressure. 1N Hydrochloric acid (ethanol solution) was added to the concentrated residue, and the mixture was concentrated under reduced pressure. The obtained solid was washed with ether to obtain the title compound (58 mg, 59%).
  • IR (ATR) cm _1 3240, 3072, 2918, 2661, 2569, 2438, 1647, 1608, 1541, 1504, 1456, 1286, 818, 748, 652, 611, 574.
  • Step 2 4- [6-[(tert-butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3-yl] benzoic acid methyl ester
  • Step 3 4- [6-[(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] benzoic acid
  • the extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • reaction mixture was filtered to remove insolubles, and the filtrate was concentrated under reduced pressure.
  • Dichloromethane (5 ml) and trifluoroacetic acid (5 ml) were added to the concentrated residue, and the mixture was stirred at room temperature for 1.5 hours.
  • Reaction mixture After concentration under reduced pressure, the concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the resulting concentrated liquid to make the liquid alkaline, and the mixture was extracted with chloroform.
  • the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure.
  • the obtained solid was washed with ether to obtain the title compound (43 mg, 30%).
  • Step 1 4 [6 — [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3 yl] 3 Fluorobenzaldehyde
  • Step 2 4-[6-[(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3-yl] 2 Fluorobenzoic acid
  • Step 3 4- [6-[(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2-Fluoro N- [3 (dimethylamino) propan 2—yl] benzamide
  • Step 4 [6— [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine-3 —yl] 2 Fluoro N— [3 (Dimethylamino) propane-1-yl] benzamide dihydrochloride
  • IR (ATR) cm _1 3048, 2670, 1621, 1608, 1508.
  • Step 1 [6— [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2 Fluoro-N-methyl-N- [2- (dimethylamino) ethyl Benzamide
  • Step 2 [6 [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine-3-yl] — 2-Fluoro N methyl N— [2— (Dimethylamino) ethyl] benzamide
  • IR (ATR) cm _1 3257, 2572, 2472, 1621, 1608, 1504.
  • Step 2 [[(2S) 1 Methylpyrrolidine-2-yl] methyl] strength rubamate Benzyl Estenole
  • Step 4 4- [6-[(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2 Fluoro-N — [[(2S) -1-Gyne 2—yl] methyl] benzamide
  • IR (ATR) cm _1 3220, 3058, 2956, 2624, 2493, 1654, 1621, 1506.
  • Step 1 4 [6 -— [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2-fluoro-N methyl-N- (l-methylbiphenyl lysine 3—yl) benzamide
  • Step 2 [6 [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine-3-yl] — 2-Fluoro N methyl N— (1-methylpyrrolidine 3-inore) benzamide 2 Hydrochloride
  • Step 5 4- [6-[(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-1-yl] 2-fluoro-N-[[(2S, 4S)- l- (tert- Butoxycarbonyl) 4 Fluoropilysine 2 yl] Methinole] benzamide
  • Step 6 4- [6 -— [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2 Fluoro-N-[[(2S, 4S) -4 Fluoropyrrolidine-2 LE] METH NORE] benzamide [0312] [Chemical 100]
  • the extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was dissolved in a very small amount of dichloromethane, and a small amount of ethyl acetate was added and allowed to stand.
  • the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (120 mg, 78%).
  • Step 2 3-Bromo-6-[(tert-butoxycarbonyl) (cyclobutyl) amino] imidazo [1,2-b] pyridazine
  • Step 3 4- [6 -— [(tert-Butoxycarbonyl) (cyclobutyl) amino] imidazo [1, 2 b] pyridazine 3-yl] benzoic acid

Abstract

A novel low molecular compound which has an action of inhibiting TNF-α production, exerts an excellent effect in a pathological model of inflammatory disease and/or auto-immune disease, has high safety, and can be orally administered is provided. A compound represented by the following general formula (I): [wherein R1 represents a hydrogen atom or a C1-C6 alkyl group, R2 represents a C1-C6 alkyl group which may have a substituent or the like, the ring A represents a benzene ring or the like, X represents a hydrogen atom or 1 to 3 groups, which may be the same or different, selected from the group consisting of a halogeno group, a C1-C6 alkyl group and the like, and Y represents a group represented by -N(R3a)C(R6aR7a)C(R8aR9a)N(R4aR5a) or the like, (R3a, R4a, R5a, R6a, R7a, R8a and R9a may be the same or different and represent a hydrogen atom, a C1-C6 alkyl group or the like)], a salt thereof or a solvate thereof, and a TNF-α production inhibitor comprising the compound, a salt thereof or a solvate thereof as an active ingredient.

Description

明 細 書  Specification
イミダゾ [1， 2— b]ピリダジン誘導体  Imidazo [1,2-b] pyridazine derivatives
技術分野  Technical field
[0001] 本発明は、新規なイミダゾ [ 1 , 2— b]ピリダジン骨格を有する TNF— a産生抑制薬 に関する。  [0001] The present invention relates to a novel TNF-a production inhibitor having an imidazo [1,2-b] pyridazine skeleton.
背景技術  Background art
[0002] 腫瘍壊死因子 alpha (TNF - a )は多彩な生理活性作用を示すことが報告され ている。一方、過剰に生産された TNF— aは、慢性関節リウマチ等の炎症性疾患及 び/又は自己免疫疾患において、病態の発症及び/又は進展に大きく関与する炎 症性サイト力インの一つであることが知られている。  [0002] Tumor necrosis factor alpha (TNF-a) has been reported to exhibit various bioactive effects. On the other hand, overproduced TNF-a is one of the inflammatory site forces that are greatly involved in the onset and / or progression of inflammatory diseases such as rheumatoid arthritis and / or autoimmune diseases. It is known that there is.
[0003] 過剰生産された TNF— aが関与する疾患としては、慢性関節リウマチ、ベーチヱッ ト病、アレルギー性皮膚炎、アトピー性皮膚炎、気管支喘息、敗血症、炎症性腸疾患 、乾癬、血栓症、肝炎、糖尿病、慢性閉塞性肺疾患、脳梗塞等の炎症性疾患及び/ 又は自己免疫疾患が報告されている。従って、 TNF α産生抑制作用を示す薬剤 は、各種炎症性疾患、自己免疫疾患の治療及び/又は予防薬としての有用性が期 待されている。  [0003] Diseases associated with overproduced TNF-a include rheumatoid arthritis, Beech's disease, allergic dermatitis, atopic dermatitis, bronchial asthma, sepsis, inflammatory bowel disease, psoriasis, thrombosis, Inflammatory diseases such as hepatitis, diabetes, chronic obstructive pulmonary disease, cerebral infarction and / or autoimmune diseases have been reported. Therefore, a drug exhibiting an inhibitory effect on TNFα production is expected to be useful as a therapeutic and / or prophylactic agent for various inflammatory diseases and autoimmune diseases.
[0004] 近年、各種炎症性疾患及び/又は自己免疫疾患に対して、抗 TNF— a作用を有 する生物薬剤による臨床での治療が試みられている。その結果、可溶性 TNF— a 受容体の融合タンパク質であるエタネルセプト（etanercept, Immunex/Wyeth) 、ならびに抗 TNF— αキメラモノクローナルヒト及びマウス抗体であるインフリキシマ ブ（infliximab, Centocor) ヽ慢性関節リウマチの治療にお!/、て劇的な有効性を 示すことが明らかになった。さらに、これらの生物製剤は、クローン病の治療において も有効性を示している（非特許文献 1)。これらのことから、 TNF - aが創薬の分子標 的として重要であることが証明された。  [0004] In recent years, various inflammatory diseases and / or autoimmune diseases have been clinically treated with biological agents having anti-TNF-a action. As a result, etanercept, a fusion protein of soluble TNF-a receptor (etanercept, Immunex / Wyeth), and anti-TNF-α chimeric monoclonal human and mouse antibody, infliximab, Centocor ヽ treatment of rheumatoid arthritis It turned out to show dramatic effectiveness! Furthermore, these biologics have also been effective in the treatment of Crohn's disease (Non-patent Document 1). These facts proved that TNF-a is important as a molecular target for drug discovery.
[0005] 一方、これら生物薬剤は高い臨床効果を持つ反面、 1 )薬剤費が極めて高額である こと、 2)感染症や悪性腫瘍等の副作用発現、 3)ペプチド性高分子化合物であるた め経口吸収性がなぐ経口投与では有効性を発揮できな!/、ことから点滴静脈内投与 又は皮下投与等の煩雑な投与方法が必要である、等の問題点が指摘されている。 そこで、力、かる問題点を克服し、かつ高い臨床効果を有する経口投与可能な低分子 抗 TNF α薬の開発が望まれている。 [0005] On the other hand, these biopharmaceuticals have high clinical effects, but 1) the cost of drugs is extremely high, 2) side effects such as infectious diseases and malignant tumors, and 3) peptide polymers. Oral administration with no oral absorbability cannot be effective! /, So intravenous infusion In addition, problems such as the need for complicated administration methods such as subcutaneous administration have been pointed out. Therefore, it is desired to develop an orally administrable small molecule anti-TNF α drug that overcomes these problems and has a high clinical effect.
[0006] これまで、 TNF— a産生抑制作用を有する化合物として、ァニリノピリミジン誘導体 [0006] So far, an anilinopyrimidine derivative has been used as a compound having a TNF-a production inhibitory action.
(特許文献 1)、イミダゾ [1, 2— a]キノキサリン誘導体 (非特許文献 2)、 1, 4 ジヒド ロー 2H ピリド [2, 3— d][l, 3]ォキサジン 2 オン誘導体 (非特許文献 3)、 1 (ピラゾール一 3—ィル） 3— (ナフタレン一 1—ィル)ゥレア誘導体（非特許文献 4)、 4 フエ二ノレ一 5 ピリジノレ一 1, 3 チアゾール誘導体（非特許文献 5)、 2 フエ二 ル一 3— (ピリジン一 4 ィル） 4— (1, 2, 3, 6 テトラヒドロピリジン一 4 ィル） 1 H ピロール誘導体 (非特許文献 6)等が報告されているが、さらに優れた効果を発 揮し、副作用が少なぐ経口投与可能で、かつ作用の持続性に優れた新規な低分子 TNF- a阻害化合物が望まれている。  (Patent Document 1), imidazo [1,2-a] quinoxaline derivative (Non-patent Document 2), 1,4 dihydro 2H pyrido [2,3-d] [l, 3] oxazine 2-one derivative (Non-Patent Document 2) 3), 1 (pyrazole 1-yl) 3- (naphthalene 1-yl) urea derivative (Non-patent document 4), 4 Pheninore 1 5 pyridinole 1, 3 thiazole derivative (Non-patent document 5) 2 Phenyl-3- (pyridine 4-yl) 4- (1, 2, 3, 6 tetrahydropyridine 4-yl) 1 H pyrrole derivative (Non-patent document 6) etc. have been reported. Further, there is a demand for novel low-molecular-weight TNF-a inhibitor compounds that have excellent effects, can be administered orally with few side effects, and have long-lasting action.
一方、生理活性を有するイミダゾ [1, 2— b]ピリダジン誘導体が報告されているが、 T NF α産生抑制作用に関する記載は無い（特許文献 2〜6、非特許文献 7〜9)。  On the other hand, imidazo [1,2-b] pyridazine derivatives having physiological activity have been reported, but there is no description regarding TNFα production inhibitory action (Patent Documents 2 to 6, Non-Patent Documents 7 to 9).
[0007] 特許文献 1:特表 2004— 523479号公報 [0007] Patent Document 1: Special Table 2004—523479
特許文献 2:国際公開第 2005/066177号パンフレット  Patent Document 2: International Publication No. 2005/066177 Pamphlet
特許文献 3:米国特許出願公開第 2004/0067948号明細書  Patent Document 3: US Patent Application Publication No. 2004/0067948
特許文献 4:国際公開第 2007/013673号ノ  Patent Document 4: International Publication No. 2007/013673
特許文献 5：国際公開第 2007/025090号ノ  Patent Document 5: International Publication No. 2007/025090
特許文献 6：米国特許出願公開第 2007/0093490号明細書  Patent Document 6: US Patent Application Publication No. 2007/0093490
非特許文献 1: Exp. Opin. Invest. Drugs, 2000, 9:103.  Non-Patent Document 1: Exp. Opin. Invest. Drugs, 2000, 9: 103.
非特許文献 2 :J. Biol. Chem. , 278(3), 1450 1456(2003).  Non-Patent Document 2: J. Biol. Chem., 278 (3), 1450 1456 (2003).
非特許文献 3:Br. J. Pharmacol. , 145(2), 178— 192(2005),  Non-Patent Document 3: Br. J. Pharmacol., 145 (2), 178-192 (2005),
非特許文献 4:J. Med. Chem. , 46(22), 4676-4686(2003).  Non-Patent Document 4: J. Med. Chem., 46 (22), 4676-4686 (2003).
非特許文献 5:J. Med. Chem. , 48(19), 5966— 5979(2005).  Non-Patent Document 5: J. Med. Chem., 48 (19), 5966-5979 (2005).
非特許文献 6:Eu. J. Pharmacol. , 506, 285— 295(2005).  Non-Patent Document 6: Eu. J. Pharmacol., 506, 285-295 (2005).
非特許文献 7 :J. Med. Chem. , 48(24), 7604— 7614(2005).  Non-Patent Document 7: J. Med. Chem., 48 (24), 7604-7614 (2005).
非特許文献 8 :J. Med. Chem. , 46(20), 4333— 4341(2003). 非特許文献 9 :J. Med. Chem. , 44 (3) , 350— 361 (2001 ) . Non-Patent Document 8: J. Med. Chem., 46 (20), 4333-4341 (2003). Non-Patent Document 9: J. Med. Chem., 44 (3), 350-361 (2001).
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0008] TNF - a産生抑制作用を示し、炎症性疾患及び/又は自己免疫疾患病態モデ ルで優れた効果を発揮し、力、つ安全性が高く経口投与が可能な新規な低分子化合 物を提供することが課題である。 [0008] A novel low molecular weight compound that exhibits TNF-a production inhibitory action, exhibits excellent effects in inflammatory diseases and / or autoimmune disease pathological models, and is highly safe and safe for oral administration It is a problem to provide.
課題を解決するための手段  Means for solving the problem
[0009] 本発明者らは上記の課題を解決するため、鋭意研究を行った結果、従来の化合物 とは異なるイミダゾ [ 1 , 2— b]ピリダジン構造を有する新規な化合物力 TNF— α産 生抑制作用を有し、マウス in vivoモデルにおいて経口投与でマウス血中 TNF— a を低下させ、副作用が少ない炎症性疾患治療剤及び/又は自己免疫疾患剤の有 効成分として用いることができることを見出し、本発明を完成するに至った。  [0009] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a novel compound power TNF-α production having an imidazo [1,2-b] pyridazine structure different from that of conventional compounds. It has been found that it can be used as an effective component of inflammatory disease therapeutic agent and / or autoimmune disease agent that has inhibitory action, reduces TNF-a in mouse blood by oral administration in mouse in vivo model, and has few side effects. The present invention has been completed.
[0010] すなわち本発明は、下記の一般式 (I)  That is, the present invention provides the following general formula (I)
[0011] [化 1]  [0011] [Chemical 1]
Figure imgf000005_0001
Figure imgf000005_0001
[0012] [式中、 R1は、水素原子又は C 1〜C6アルキル基を示し、 [Wherein R 1 represents a hydrogen atom or a C 1 -C 6 alkyl group,
R2は、置換基を有していてもよい C 1〜C6アルキル基又は C3〜C7シクロアルキル 基を示し、 R 2 represents an optionally substituted C1-C6 alkyl group or C3-C7 cycloalkyl group,
環 Aは、ベンゼン環、或いは、 5又は 6員の芳香族複素環を示し、  Ring A represents a benzene ring or a 5- or 6-membered aromatic heterocycle,
Xは、水素原子であるか、或いは、同一又は異なって、ハロゲノ基、 C 1〜C6アルキ ル基、ハロゲノ C 1〜C6アルキル基、 C 1〜C6アルコキシ C 1〜C6アルキル基、水酸 基、 C1〜C6アルコキシ基、ハロゲノ C1〜C6アルコキシ基、 C1〜C6ァノレコキシ C1 〜C6アルコキシ基、カルボキシ基、 C1〜C6アルコキシカルボニル基、シァノ基、力 ルバモイル基、 N—モノ（C1〜C6アルキル）力ルバモイル基、 N, N—ジ（C1〜C6ァ ルキル）力ルバモイル基、アミノ基、モノ（C1〜C6アルキル）アミノ基、ジ（C1〜C6ァ ルキル）アミノ基、 C1〜C6アルキルチオ基、 C1〜C6アルキルスルホニル基及びニト 口基からなる群より選ばれる 1〜3個の基を示し、 X is a hydrogen atom, or the same or different, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a hydroxy acid Group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group, C1-C6 anorecoxy C1-C6 alkoxy group, carboxy group, C1-C6 alkoxycarbonyl group, cyano group, force rumoyl group, N-mono (C1-C6 alkyl) ) Force rubermoyl group, N, N-di (C1-C6 alkyl) force rubermoyl group, amino group, mono (C1-C6 alkyl) amino group, di (C1-C6 alkyl) amino group, C1-C6 alkylthio group 1 to 3 groups selected from the group consisting of a C1-C6 alkylsulfonyl group and a nitro group;
Yは、下記の式（a)〜 又は（V) Y is the following formula (a) to or (V)
[0013] [化 2] [0013] [Chemical 2]
Figure imgf000006_0001
Figure imgf000006_0001
(V)  (V)
[0014] (式中、 R3a、 R3b、 R3c、 R3d、 R3e、 R3f、 R3g及び R3vは、同- -又は異なって、水素原子 又は C1〜C6アルキル基を示し、 (In the formula, R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3v are the same--or different and represent a hydrogen atom or a C1-C6 alkyl group,
R4a、 R5a、 R4b、 R5b、 R4c、 R5c、 R4d、 R5d、 R4h、 R5h、 R4i、 R5i、 R4j及び R5jは、同一又は 異なって、水素原子、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C1〜C6 アルコキシ C1〜C6アルキル基、C3〜C7シクロアルキル基又は C3〜C7シクロアル キル C1〜C6アルキル基を示す力、、或いは、 R4aと R5a、 R4bと R5b、 R4cと R5c、 R4dと R5d、 R4hと R5h、 R4iと R5i、及び R4jと R5jは、同一又 は異なって、 2つの基が結合する窒素原子と一体化して 4〜7員の含窒素脂肪族複 素環 (この含窒素脂肪族複素環は、ハロゲノ基、 C1〜C6アルキル基、ハロゲノ Cl〜 C6ァノレキノレ基、 C1〜C6アルコキシ C1〜C6アルキル基、水酸基、 C1〜C6アルコ キシ基、ハロゲノ C1〜C6アルコキシ基及び C1〜C6アルコキシ C1〜C6アルコキシ 基からなる群より選ばれる基で 1〜3個置換されてもよい。）を形成してもよいことを示 し、 R 4a , R 5a , R 4b , R 5b , R 4c , R 5c , R 4d , R 5d , R 4h , R 5h , R 4i , R 5i , R 4j and R 5j are the same or different and are hydrogen atoms C1-C6 alkenoquinole group, halogeno C1-C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group, C3-C7 cycloalkyl group or C3-C7 cycloalkyl C1-C6 alkyl group, or R 4a and R 5a , R 4b and R 5b , R 4c and R 5c , R 4d and R 5d , R 4h and R 5h , R 4i and R 5i , and R 4j and R 5j are the same or different, Combined with the nitrogen atom to which the two groups are bonded, a 4- to 7-membered nitrogen-containing aliphatic heterocyclic ring (this nitrogen-containing aliphatic heterocyclic ring is a halogeno group, a C1-C6 alkyl group, a halogeno Cl-C6 anolequinole group, C1-C6 alkoxy C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group, and C1-C6 alkoxy group substituted with 1-3 groups selected from C1-C6 alkoxy group ) May be formed, and
R4e、 R4f及び R4gは、同一又は異なって、水素原子、 C1〜C6アルキル基、ハロゲノ C ；!〜 C6ァノレキノレ基、 C1〜C6アルコキシ C1〜C6アルキル基、 C3〜C7シクロアルキ ル基、 C 3〜 C 7シクロアルキル C；!〜 C 6アルキル基又はフエニル C；!〜 C 6アルキノレ 基（このフエニル C1〜C6アルキル基のフエニル基は、ハロゲノ基、 C1〜C6ァノレキノレ 基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換され ていてもよい。）を示し、 R 4e , R 4f and R 4g are the same or different and are a hydrogen atom, a C1-C6 alkyl group, a halogeno C;! -C6 alkanoleno group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkyl group, C 3 to C 7 cycloalkyl C;! To C 6 alkyl group or phenyl C;! To C 6 alkynole group (the phenyl group of this phenyl C1 to C6 alkyl group is a halogeno group, a C1 to C6 alkenyl group, a hydroxyl group and C1 1 to 3 groups may be substituted with a group selected from the group consisting of -C6 alkoxy groups).
R6a、 R6b、 R7a、 R7b、 R8a、 R8b、 R9a、 R9b、 R10b及び Rubは、同一又は異なって、水素 原子、ハロゲノ基、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C1〜C6ァ ルコキシ C1〜C6アルキル基、水酸基、 C1〜C6アルコキシ基、ハロゲノ C1〜C6ァ ルコキシ基又は C1〜C6アルコキシ C1〜C6アルコキシ基を示し、 R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10b and R ub are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 anorequinole group, a halogeno C1 -C6 alkyl group, C1-C6 alkyloxy, C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy C1-C6 alkoxy group,
J 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 3h、 R13l、 R13j、 R13v、 R14c、 R14d、 R14e、 R14f、 R14g、 R14h、 R14l、 R14j及び R14vは、同一 又は異なって、水素原子、ハロゲノ基、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アル キル基、 C1〜C6アルコキシ C1〜C6アルキル基、水酸基、 C1〜C6アルコキシ基、 ハロゲノ C1〜C6アルコキシ基又は C1〜C6アルコキシ C1〜C6アルコキシ基を示し k、 1、 m、 n、 o及び pは、それぞれ、 0、 1又は 2を示し、 qは、 1又は 2を示し、 J, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_ 3h, R 13l, R 13j, R 13v, R 14c, R 14d, R 14e, R 14f , R 14g , R 14h , R 14l , R 14j and R 14v are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 arnolequinole group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 An alkyl group, a hydroxyl group, a C1-C6 alkoxy group, a halogeno C1-C6 alkoxy group or a C1-C6 alkoxy C1-C6 alkoxy group, and k, 1, m, n, o and p are 0, 1 or 2, respectively. Q represents 1 or 2,
Vは、モルホリノ基を示す。）で表されるいずれか 1つの基を示す。 ]で表される化合物 、その塩又はそれらの溶媒和物を提供する。  V represents a morpholino group. ) Represents one of the groups represented. Or a salt or a solvate thereof.
さらに、本発明は、以下の（1)〜（5) Furthermore, the present invention provides the following (1) to (5)
(1)上記一般式 (I)で表される化合物、その塩又はそれらの溶媒和物を有効成分とし て含有する医薬、又は医薬を製造するための一般式 (I)で表される化合物、その塩 又はそれらの溶媒和物の使用； (1) The compound represented by the above general formula (I), a salt thereof or a solvate thereof as an active ingredient Or the use of a compound represented by the general formula (I), a salt thereof or a solvate thereof for producing a medicament;
(2)上記一般式 (I)で表される化合物を有効成分として含有する TNF— a産生抑制 剤；  (2) a TNF-a production inhibitor comprising a compound represented by the above general formula (I) as an active ingredient;
(3)上記一般式 (I)で表される化合物を有効成分として含有する炎症性疾患及び/ 又は自己免疫性疾患の治療剤及び/又は予防剤；  (3) A therapeutic and / or prophylactic agent for inflammatory diseases and / or autoimmune diseases comprising the compound represented by the general formula (I) as an active ingredient;
(4)上記一般式 (I)で表される化合物を有効成分として含有する慢性関節リウマチ治 療薬;及び  (4) a therapeutic agent for rheumatoid arthritis comprising a compound represented by the above general formula (I) as an active ingredient; and
(5)上記一般式 (I)で表される、その塩又はそれらの溶媒和物と、免疫抑制剤、免疫 抑制に用いる抗体、拒絶反応治療薬、非ステロイド性抗炎症薬 (NSAIDs)及びステ ロイド薬から選択される 1種又は 2種以上を組み合わせてなる医薬；  (5) A salt or solvate thereof represented by the above general formula (I), an immunosuppressant, an antibody used for immunosuppression, a rejection treatment, a nonsteroidal anti-inflammatory drug (NSAIDs) and a steroid A pharmaceutical comprising one or more selected from Lloyd's drugs;
の各々を提供するものである。  Is to provide each of them.
発明の効果  The invention's effect
[0015] 本発明のイミダゾ [ 1 , 2— b]ピリダジン誘導体は、経口投与で TNF— aの産生を 抑制することから、 TNF α産生に起因する各種疾患、例えば慢性関節リウマチ等 の炎症性疾患及び/又は自己免疫性疾患の予防及び/又は治療を可能とする。 発明を実施するための最良の形態  [0015] Since the imidazo [1, 2-b] pyridazine derivative of the present invention suppresses the production of TNF-a by oral administration, various diseases caused by TNFα production, such as inflammatory diseases such as rheumatoid arthritis, etc. And / or enables prevention and / or treatment of autoimmune diseases. BEST MODE FOR CARRYING OUT THE INVENTION
[0016] 以下に本明細書中の置換基について説明する。 [0016] The substituents in the present specification will be described below.
[0017] ( 1 ) C 1〜C6アルキル基とは、炭素数;!〜 6の直鎖状又は分枝鎖状の飽和炭化水 素からなる一価の基を示し、例えば、メチル基、ェチル基、 n プロピル基、イソプロ ピル基、 n ブチル基、 1ーメチルー n プロピル基、 2—メチルー n プロピル基、 te rtーブチノレ基、 n—ペンチノレ基、 1ーメチノレー n ブチノレ基、 2—メチノレー n ブチノレ 基、 3 メチルー n ブチル基、 1 , 1 ジメチルー n プロピル基、 2, 2 ジメチルー n プロピル基、 1 , 2—ジメチルー n プロピル基、 1ーェチルー n プロピル基、 n 一へキシル基、 1ーメチルー n ペンチル基、 2 メチルー n ペンチル基、 3 メチ ノレ n—ペンチル基、 4ーメチルー n—ペンチル基、 1 , 1 ジメチルー n ブチル基 、 2, 2—ジメチノレー n ブチノレ基、 3, 3—ジメチノレー n ブチノレ基、 1 , 2—ジメチノレ n ブチル基、 1 , 3—ジメチルー n ブチル基、 2, 3—ジメチルー n ブチル基、 1ーェチルー n ブチル基、 2—ェチルー n ブチル基及び 1 （イソプロピル） n プロピル基等が挙げられる。 [0017] (1) C1-C6 alkyl group refers to a monovalent group consisting of linear or branched saturated hydrocarbons having carbon number;! -6, for example, methyl group, ethyl Group, n-propyl group, isopropyl group, n-butyl group, 1-methyl-n-propyl group, 2-methyl-n-propyl group, ter-butinore group, n-pentinole group, 1-methylenole n-butinore group, 2-methinole n-butinore group, 3 Methyl-n butyl group, 1,1 dimethyl-n propyl group, 2,2 dimethyl-n propyl group, 1,2-dimethyl-n propyl group, 1-ethyl-n propyl group, n-hexyl group, 1-methyl-n pentyl group, 2 Methyl-n pentyl group, 3 methylolene n-pentyl group, 4-methyl-n-pentyl group, 1,1 dimethyl-n butyl group, 2,2-dimethinole n butynole group, 3,3-dimethinole n butynole group, 1, 2— Zimechi Les n-butyl group, 1, 3-dimethyl-n-butyl group, 2, 3-dimethyl-n-butyl group, Examples include 1-ethyl-n-butyl group, 2-ethyl-n-butyl group, and 1 (isopropyl) n-propyl group.
[0018] (2) C3〜C7シクロアルキル基とは、炭素数 3〜7の環状飽和炭化水素環から形成 される一価の基を示し、例えばシクロプロピル基、シクロブチル基、シクロペンチル基 、シクロへキシル基及びシクロへプチル基が挙げられる。  [0018] (2) The C3 to C7 cycloalkyl group refers to a monovalent group formed from a cyclic saturated hydrocarbon ring having 3 to 7 carbon atoms, and includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexane. A xyl group and a cycloheptyl group are mentioned.
[0019] (3) 5又は 6員の芳香族複素環とは、環の構成元素として窒素原子、酸素原子及び 硫黄原子から選ばれるヘテロ原子を 1又は 2個含む芳香族複素環を示す。 5又は 6 員の芳香族複素環としては、例えばピロール環、フラン環、チォフェン環、ピラゾーノレ 環、イミダゾール環、ォキサゾール環、イソォキサゾール環、チアゾール環、イソチア ゾール環、ピリジン環、ピリダジン環、ピリミジン環及びピラジン環等を挙げることがで きる。  [0019] (3) The 5- or 6-membered aromatic heterocycle refers to an aromatic heterocycle containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as constituent elements of the ring. Examples of the 5- or 6-membered aromatic heterocycle include a pyrrole ring, a furan ring, a thiophene ring, a pyrazonole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a pyridine ring, a pyridazine ring, and a pyrimidine ring. Examples thereof include a pyrazine ring.
[0020] (4)ハロゲノ基とは、フルォロ基、クロ口基、ブロモ基及びィォド基を示す。  [0020] (4) The halogeno group refers to a fluoro group, a black mouth group, a bromo group and an iodo group.
[0021] (5)ハロゲノ C1〜C6アルキル基とは、上記のハロゲノ基を置換基として有する C1 〜C6アルキル基を示し、ハロゲノ基の数は 1個であっても 2個以上であってもよぐ 2 個以上である場合の各ハロゲノ基の種類は、同一又は異なっていてもよい。ハロゲノ C1〜C6アルキル基の具体例としては、フルォロメチル基、ジフルォロメチル基、トリ フルォロメチル基、 1 フルォロェチル基、 2—フルォロェチル基、 2—クロロェチノレ 基、 2—ブロモェチル基、（1 , 1ージフルォロ）ェチル基、（1 , 2—ジフルォロ）ェチル 基、（2, 2, 2—卜リフノレ才口）ュチノレ基、 (1 , 1 , 2, 2—テ卜ラフノレ才口）ュチノレ基、 (1 , 1 , 2, 2, 2—ペンタフルォ口）ェチル基、 1 フルォロプロピル基、 1 , 1ージフルォロ プロピル基、 2, 2 ジフルォロプロピル基、 3 フルオロー n プロピル基、（3, 3, 3 トリフルォロ）—n—プロピル基、 4 フルオロー n ブチル基、（4, 4, 4 トリフノレ ォ口）— n ブチル基、 5—フルオロー n—ペンチル基、（5, 5, 5—トリフルォロ）—n ペンチル基、 6—フルオロー n へキシル基及び（6, 6, 6—トリフルォロ） n へ キシル基等を挙げることができる。 [0021] (5) The halogeno C1-C6 alkyl group means a C1-C6 alkyl group having the above-mentioned halogeno group as a substituent, and the number of halogeno groups may be one or two or more. The types of each halogeno group in the case of 2 or more may be the same or different. Specific examples of the halogeno C1-C6 alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 1 fluoroethyl group, a 2-fluoroethyl group, a 2-chloroethynole group, a 2-bromoethyl group, a (1,1-difluoro) ethyl group, (1,2, -difluoro) ethyl group, (2,2,2--Lifnore talent) Uchinole group, (1,1,2,2-Terafugnole mouthpiece) Tuchinole group, (1,1,2,2, 2,2-pentafluoro) ethyl group, 1 fluoropropyl group, 1,1-difluoropropyl group, 2,2 difluoropropyl group, 3 fluoro-n-propyl group, (3, 3, 3 trifluoro) -n-propyl group, 4 Fluoro-n-butyl group, (4, 4, 4 trifluoro group) — n butyl group, 5-fluoro-n-pentyl group, (5, 5, 5-trifluoro) -n pentyl group, 6-fluoro-n hexyl group And (6, 6, 6 —Trifluoro) n Hexyl group and the like can be mentioned.
[0022] (6) C1〜C6アルコキシ基とは、上記の C1〜C6アルキル基から形成される C 1〜C 6アルキルォキシ基を示し、例えば、メトキシ基、エトキシ基、 n プロポキシ基、イソプ 口ポキシ基、 n—ブトキシ基、 1ーメチルー n—プロポキシ基、 2—メチルー n プロボ キシ基、 tert ブトキシ基、 n ペンチルォキシ基、 1ーメチルー n ブトキシ基、 2— メチルー n—ブトキシ基、 3—メチルー n—ブトキシ基、 1 , 1 ジメチルー n—プロポキ シ基、 2, 2—ジメチノレー n プロポキシ基、 1 , 2—ジメチノレー n プロポキシ基、 1 ェチルー n プロポキシ基、 n へキシルォキシ基、 1ーメチルー n ペンチルォキシ 基、 2 メチルー n ペンチルォキシ基、 3 メチルー n ペンチルォキシ基、 4ーメ チルー n ペンチルォキシ基、 1 , 1 ジメチルー n ブトキシ基、 2, 2—ジメチルー n ブトキシ基、 3, 3—ジメチノレー n ブトキシ基、 1 , 2—ジメチノレー n ブトキシ基、 1 , 3 ジメチノレー n ブトキシ基、 2, 3 ジメチノレー n ブトキシ基、 1ーェチノレー n— ブトキシ基、 2—ェチルー n ブトキシ基及び 1 （イソプロピル） n プロポキシ基 等を挙げること力 Sでさる。 [0022] (6) The C1-C6 alkoxy group refers to a C1-C6 alkyloxy group formed from the above-mentioned C1-C6 alkyl group, and includes, for example, a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group. Group, n-butoxy group, 1-methyl-n-propoxy group, 2-methyl-n Xyl group, tert butoxy group, n pentyloxy group, 1-methyl-n butoxy group, 2-methyl-n-butoxy group, 3-methyl-n-butoxy group, 1,1 dimethyl-n-propoxy group, 2,2-dimethylenole n propoxy Group, 1,2-dimethylolene n propoxy group, 1 ethyl n propoxy group, n hexyloxy group, 1-methyl n pentyloxy group, 2 methyl n pentyloxy group, 3 methyl n pentyloxy group, 4-methyl n pentyloxy group, 1, 1 Dimethyl-n butoxy group, 2,2-Dimethyl-n butoxy group, 3,3-Dimethylolene butoxy group, 1,2-Dimethylolene n-Butoxy group, 1,3 Dimethylolene n-Butoxy group, 2,3 Dimethylolene n-Butoxy group, 1 -Ethynole n-butoxy group, 2-ethyl- n butoxy group and 1 (isopropyl) n propoxy group, etc. Raise your power with S.
[0023] (7)じ1〜じ6ァルコキシじ1〜じ6ァルキル基とは、上記の C1〜C6アルコキシ基で 1 個置換された C1〜C6アルキル基を示し、例えば、メトキシメチル基、エトキシメチノレ 基、 n プロポキシメチル基、イソプロポキシメチル基、 n ブトキシメチル基、 tert— ブトキシメチル基、 n—ペンチルォキシメチル基、 n へキシルォキシメチル基、 1ーメ トキシェチル基、 2 メトキシェチル基、 2 エトキシェチル基、 3 メトキシー n プロ ピル基、 3—エトキシ n—プロピル基、 4ーメトキシー n ブチル基、 4 エトキシ n ブチル基、 5—メトキシー n ペンチル基及び 6—メトキシ n へキシル基等を挙 げること力 Sでさる。 [0023] (7) 1 to 6 alkyloxy 1 to 6 alkyl groups refers to a C1-C6 alkyl group substituted by one of the above C1-C6 alkoxy groups, and include, for example, a methoxymethyl group, ethoxymethylol Group, n propoxymethyl group, isopropoxymethyl group, n butoxymethyl group, tert-butoxymethyl group, n-pentyloxymethyl group, n-hexyloxymethyl group, 1-methoxychetyl group, 2 methoxyethyl group, 2 List ethoxyethyl, 3-methoxy-n-propyl, 3-ethoxy-n-propyl, 4-methoxy-n-butyl, 4-ethoxy-n-butyl, 5-methoxy-n-pentyl and 6-methoxy-n-hexyl. Touch with force S.
[0024] (8)ハロゲノ C1〜C6アルコキシ基としては、上記のハロゲノ基を置換基として有す る C1〜C6アルキルォキシ基を示し、ハロゲノ基の数は 1個であっても 2個以上であつ てもよく、 2個以上である場合の各ハロゲノ基の種類は、同一又は異なっていてもよい 。ハロゲノ C1〜C6アルコキシ基の具体例としては、フルォロメトキシ基、ジフルォロメ トキシ基、トリフルォロメトキシ基、 1 フルォロエトキシ基、 2—フルォロエトキシ基、 2 —クロ口エトキシ基、 2—ブロモエトキシ基、（1 , 1—ジフルォロ）エトキシ基、（1 , 2 - ジフルォロ）エトキシ基、（2, 2, 2—トリフルォロ）エトキシ基、（1 , 1 , 2, 2—テトラフル ォロ）エトキシ基、（1 , 1 , 2, 2, 2—ペンタフルォ口）エトキシ基、 1 フルォロプロポキ n プロポキシ基、（3, 3, 3—トリフノレオ口） n プロポキシ基、 4ーフノレオロー n ブトキシ基、 （4, 4, 4 トリフルォロ）—n—ブトキシ基、 5—フルオロー n—ペンチ ノレォキシ基、 （5, 5, 5—トリフルォロ） n—ペンチルォキシ基、 6—フルオロー n へ キシルォキシ基及び（6, 6, 6—トリフルォロ） n へキシルォキシ基等を挙げること ができる。 [0024] (8) The halogeno C1-C6 alkoxy group is a C1-C6 alkyloxy group having the above-mentioned halogeno group as a substituent, and the number of halogeno groups is one or two or more. The type of each halogeno group in the case of two or more may be the same or different. Specific examples of the halogeno C1-C6 alkoxy group include a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 1 fluoroethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group, (1, 1-difluoro) ethoxy group, (1,2-difluoro) ethoxy group, (2,2,2-trifluoro) ethoxy group, (1,1,2,2,2-tetrafluoro) ethoxy group, (1,1, 2, 2, 2-pentafluoro mouth) ethoxy group, 1 fluoropropoxy n propoxy group, (3, 3, 3-trifunoleo mouth) n propoxy group, 4-funoleolone n Butoxy group, (4, 4, 4 trifluoro) -n-butoxy group, 5-fluoro-n-pentynoleoxy group, (5, 5, 5-trifluoro) n-pentyloxy group, 6-fluoro n-hexyloxy group and (6 , 6, 6-trifluoro) n-hexyloxy group and the like.
[0025] (9)じ1〜じ6ァルコキシじ1〜じ6ァルコキシ基とは、上記の C1〜C6アルコキシ基 で 1個置換された C1〜C6アルキルォキシ基を示し、例えば、メトキシメトキシ基、エト キシメトキシ基、 2 メトキシエトキシ基、 2 エトキシエトキシ基、 3 メトキシー n プ 口ポキシ基、 3—エトキシー n プロポキシ基、 4ーメトキシー n ブトキシ基、 4 エト キシー n ブトキシ基、 5—メトキシー n ペンチルォキシ基及び 6—メトキシー n へ キシルォキシ基等を挙げることができる。  (9) 1 to 6 alkyloxy 1 to 6 alkoxy groups are C1-C6 alkyloxy groups substituted by one of the above-mentioned C1-C6 alkoxy groups, such as methoxymethoxy group, Xymethoxy group, 2 methoxyethoxy group, 2 ethoxyethoxy group, 3 methoxy n propoxy group, 3-ethoxy n propoxy group, 4-methoxy n butoxy group, 4 ethoxy n butoxy group, 5-methoxy n pentyloxy group and 6— A methoxy-n-hexyloxy group and the like can be mentioned.
[0026] (10) N モノ（C1〜C6アルキル）力ルバモイル基とは、力ルバモイル基の窒素原 子上の水素原子が、上記の C1〜C6アルキル基で 1個置換された力ルバモイル基を 示し、例えば N （メチル）力ルバモイル基、 N （ェチル）力ルバモイル基、 N— (n- プロピル）力ルバモイル基、 N （イソプロピル）力ルバモイル基、 N—（n ブチル）力 ノレバモイル基、 N （イソブチル）力ルバモイル基、 N—（tert ブチル）力ルバモイル 基、 N—（n ペンチル）力ルバモイル基及び N—（n へキシル）力ルバモイル基等 が挙げられる。  [0026] (10) N mono (C1-C6 alkyl) rubamoyl group is a rubamoyl group in which one hydrogen atom on the nitrogen atom of the rubamoyl group is substituted with one of the above C1-C6 alkyl groups. For example, N (methyl) force rubamoyl group, N (ethyl) force rubamoyl group, N— (n-propyl) force rubamoyl group, N (isopropyl) force rubamoyl group, N— (n butyl) force norberamoyl group, N ( Isobutyl) -powered rubermoyl group, N- (tert-butyl) -powered rubermoyl group, N- (n-pentyl) -powered rubermoyl group, and N- (n-hexyl) -powered rubermoyl group.
[0027] (11) N, N ジ（C1〜C6アルキル）力ルバモイル基とは、力ルバモイル基の窒素 原子上の水素原子が、同一又は異なった、上記の C1〜C6アルキル基で 2個置換さ れたカルバモイル基を示し、例えばジメチルカルバモイル基、 N—ェチルー N メチ ノレ力ルバモイル基、ジェチルカルバモイル基、 N メチルー N—（n プロピル）カル バモイル基、 N ェチルー N—（n プロピル）力ルバモイル基、ジ（n プロピル）力 ノレバモイル基、ジ（イソプロピル）力ルバモイル基、 N イソプロピル N メチルカル バモイル基、ジ（n ブチル）力ルバモイル基、 N—（n ペンチル） N メチルカル バモイル基及び N— (n へキシル) N メチルカルバモイル基等を挙げることがで きる。  [11] (11) N, N di (C1-C6 alkyl) force rubamoyl group, the hydrogen atom on the nitrogen atom of force rubamoyl group is the same or different, and is substituted by the above C1-C6 alkyl group For example, dimethylcarbamoyl group, N-ethyl-N methinole rubamoyl group, jetyl carbamoyl group, N-methyl-N- (n propyl) carbamoyl group, N ethyl-N- (n propyl) rubamoyl group Group, di (n propyl) force norberamoyl group, di (isopropyl) force rubermoyl group, N isopropyl N methylcarbamoyl group, di (n butyl) force rubermoyl group, N— (n pentyl) N methylcarbamoyl group and N— (n Hexyl) N methylcarbamoyl group and the like.
[0028] (12)モノ（C1〜C6アルキル）ァミノ基とは、上記の C1〜C6アルキル基で 1個置換 されたアミノ基を示し、例えばメチルァミノ基、ェチルァミノ基、 n プロピルアミノ基、 イソプロピルアミノ基、 n ブチルァミノ基、 （2—メチルー n ブチル）アミノ基、 tert— ブチルァミノ基、 n ペンチルァミノ基及び n へキシルアミノ基等を挙げることができ [0028] (12) The mono (C1-C6 alkyl) amino group means an amino group substituted by one of the above-mentioned C1-C6 alkyl groups, for example, methylamino group, ethylamino group, n-propylamino group, And isopropylamino group, n-butylamino group, (2-methyl-n-butyl) amino group, tert-butylamino group, n-pentylamino group and n-hexylamino group.
[0029] (13)ジ（C1〜C6アルキル）アミノ基としては、同一又は異なった、上記の C1〜C6 アルキル基で 2個置換されたアミノ基を示し、例えばジメチルァミノ基、ジェチルァミノ 基、ジ (n—プロピル）アミノ基、ジ (n ブチル）アミノ基、 N メチルー N ェチルアミ ノ基、 N メチル N— (n プロピル）アミノ基、 N メチル N— (イソプロピル）アミ ノ基、 N— (n ブチル） N メチルァミノ基、 N メチルー N— (n—ペンチル）ァミノ 基及び N—（n へキシル） N メチルアミノ基等を挙げることができる。 (13) The di (C1-C6 alkyl) amino group is the same or different amino group substituted with two of the above-mentioned C1-C6 alkyl groups. For example, dimethylamino group, jetylamino group, di ( n-propyl) amino group, di (n-butyl) amino group, N-methyl-N-ethylamino group, N-methyl N- (n-propyl) amino group, N-methyl N- (isopropyl) amino group, N- (n-butyl) N methylamino group, N methyl-N- (n-pentyl) amino group, N- (n hexyl) N methylamino group and the like can be mentioned.
[0030] (14) C1〜C6アルキルチオ基としては、上記の C1〜C6アルキル基から形成され る C1〜C6アルキルチオ基を示し、例えばメチルチオ基、ェチルチオ基、 n プロピ ノレチォ基、イソプロピルチオ基、 n ブチルチオ基、 2—メチルー n ブチルチオ基、 tert ブチルチオ基、 n ペンチルチオ基及び n へキシルチオ基等が挙げられる [0030] (14) The C1-C6 alkylthio group represents a C1-C6 alkylthio group formed from the above-mentioned C1-C6 alkyl group. For example, a methylthio group, an ethylthio group, an n-propinoretio group, an isopropylthio group, an n Examples include butylthio group, 2-methyl-n butylthio group, tert butylthio group, n pentylthio group, and n hexylthio group.
〇 Yes
[0031] (15) C1〜C6アルキルスルホニル基としては、例えばメタンスルホニル基、エタンス ノレホニノレ基、 n プロピノレスノレホニノレ基、イソプロピノレスノレホニノレ基、 n ブチノレスノレ ホニノレ基、 2—メチノレー n ブチノレスノレホニノレ基、 tert ブチノレスノレホニノレ基、 n ぺ ンチルスルホニル基及び n へキシルスルホニル基等が挙げられる。  [0031] (15) Examples of the C1-C6 alkylsulfonyl group include a methanesulfonyl group, ethanesnorehoninore group, n-propinolesnorehoninore group, isopropinoresnorehoninore group, n-butinoresnorehoninore group, 2-methinoleen n Examples include butinolesnorehoninole group, tertbutinoresnorehoninole group, npentylsulfonyl group, nhexylsulfonyl group and the like.
[0032] (16) C3〜C7シクロアルキル C1〜C6アルキル基とは、上記 C3〜C7シクロァルキ ル基で 1個置換された C1〜C6アルキル基を示し、例えばシクロプロピルメチル基、 2 ーシクロプロピルェチル基、 3—シクロプロピル n—プロピル基、 4ーシクロプロピノレ n ブチル基、 5—シクロプロピル—n—ペンチル基、 6—シクロプロピル—n へ キシル基、シクロブチルメチル基、 2 シクロブチルェチル基、 3 シクロブチルー n プロピル基、 4ーシクロブチルー n ブチル基、 5—シクロブチルー n ペンチル基 、 6 シクロブチルー n へキシル基、シクロペンチルメチル基、 2 シクロペンチル ェチル基、 3—シクロペンチルー n プロピル基、 4ーシクロペンチルー n ブチル基 、 5—シクロペンチルー n ペンチル基、 6—シクロペンチルー n へキシル基、シクロ へキシルメチル基、 2 シクロへキシルェチル基、 3 シクロへキシルー n プロピル 基、 4ーシクロへキシルー n ブチル基、 5—シクロへキシルー n ペンチル基及び 6 シクロへキシル n へキシル基等が挙げられる。 [0032] (16) C3-C7 cycloalkyl The C1-C6 alkyl group refers to a C1-C6 alkyl group substituted by one of the above C3-C7 cycloalkyl groups, such as a cyclopropylmethyl group, 2-cyclopropyl Ethyl group, 3-cyclopropyl n-propyl group, 4-cyclopropinole n butyl group, 5-cyclopropyl-n-pentyl group, 6-cyclopropyl-n hexyl group, cyclobutylmethyl group, 2 cyclobutyl Ethyl group, 3 cyclobutyl-n propyl group, 4-cyclobutyl-n butyl group, 5-cyclobutyl-n pentyl group, 6 cyclobutyl-n hexyl group, cyclopentylmethyl group, 2 cyclopentylethyl group, 3-cyclopentyl-n propyl group, 4-cyclopentyl -N Butyl group, 5-cyclopentyl-n pentyl group, 6-cyclopentyl-n-hexyl group, cyclohexyl Methyl group, 2 cyclohexylethyl group, 3 cyclohexylene n propyl Group, 4-cyclohexylene n butyl group, 5-cyclohexylene n pentyl group, 6 cyclohexyl n hexyl group and the like.
[0033] (17) 4〜7員の含窒素脂肪族複素環とは、環を構成する元素として最低 1個の窒 素原子を含み、さらに、窒素原子、酸素原子及び硫黄原子から選ばれるヘテロ原子 を 1個含んでもよい 4〜7員の含窒素脂肪族複素環を示す。 4〜7員の含窒素脂肪族 複素環としては、例えばァゼチジン環、ピロリジン環、ォキサゾリジン環、ォキサゾリン 環、チアゾリジン環、イミダゾリジン環、ピぺリジン環、ピぺラジン環、モルホリン環、チ オモルホリン環、ホモピぺリジン環、 [1 , 4]ジァゼパン環、 [1 , 4]ォキサゼパン環及 び [1 , 4]チアゼパン環等を挙げることができる。 [0033] (17) A 4- to 7-membered nitrogen-containing aliphatic heterocyclic ring includes at least one nitrogen atom as an element constituting the ring, and is further selected from a nitrogen atom, an oxygen atom, and a sulfur atom. A 4- to 7-membered nitrogen-containing aliphatic heterocyclic ring which may contain one atom is shown. Examples of the 4- to 7-membered nitrogen-containing aliphatic heterocycle include azetidine ring, pyrrolidine ring, oxazolidine ring, oxazoline ring, thiazolidine ring, imidazolidine ring, piperidine ring, piperazine ring, morpholine ring, and thiomorpholine ring. , Homopiperidine ring, [1,4] diazepan ring, [1,4] oxazepan ring, and [1,4] thiazepan ring.
(17 2)モルホリノ基とは、 2 モノレホリニノレ基、 3 モルホリニル基又は 4 モルホ リニル基を示す。  (17 2) The morpholino group represents a 2 monomorpholinole group, a 3 morpholinyl group or a 4 morpholinyl group.
[0034] (18)置換基を有していてもよい C1〜C6アルキル基とは、無置換又は置換 C1〜C 6アルキル基を示し、置換 C1〜C6アルキル基としては、同一又は異なって、ハロゲノ 基、 C3〜C7シクロアルキル基、フエニル基（このフエニル基は、ハロゲノ基、 C1〜C 6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3 個置換されていてもよい。）、 5又は 6員の芳香族複素環基 (この芳香族複素環基の 芳香族複素環は、、ハロゲノ基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキ シ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、 4〜7員の脂肪族 複素環基 (この脂肪族複素環基の脂肪族複素環は、ハロゲノ基、 C1〜C6アルキル 基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換され ていてもよい。）、 4〜7員の脂肪族複素環基— CO 基 (この脂肪族複素環基は、ハ ロゲノ基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選 ばれる基で 1〜3個置換されていてもよい。）、水酸基、 C1〜C6アルコキシ基、ハロ ゲノ C1〜C6アルコキシ基、 C3〜C7シクロアルキルォキシ基、フエニル C1〜C6ァ ルコキシ基（このフエニル C1〜C6アルコキシ基のフエニル基は、ハロゲノ基、 C1〜C 6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3 個置換されていてもよい。）、フエノキシ基（このフエノキシ基は、ハロゲノ基、 C1〜C6 アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個 置換されていてもよい。）、アミノ基、モノ（C1〜C6アルキル）アミノ基、ジ（C1〜C6ァ ルキル）アミノ基、 C2〜C6アルカノィルァミノ基、ベンゾィルァミノ基（このベンゾィル ァミノ基のベンゾィル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6 アルコキシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、ベンジノレ アミノ基（このベンジルァミノ基のベンジル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水 酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換されていて もよい。）、 C1〜C6アルキルチオ基、 C1〜C6アルキルスルフィニル基、 C1〜C6ァ ルキルスルホニル基、フエ二ルチオ基（このフエ二ルチオ基のフエニル基は、ノ、ロゲノ 基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる 基で 1〜3個置換されていてもよい。）、フエニルスルフィニル基（このフエニルスルフィ ニル基のフエニル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6アル コキシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、及びフエニル スルホニル基（このフエニルスルホニル基のフエニル基は、ハロゲノ基、 C1〜C6アル キル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換 されて!/、てもよ!/、。 )力、らなる群より選ばれる基で 1〜3個置換された C1〜C6アルキ ノレ基を示す。 (18) The C1-C6 alkyl group which may have a substituent represents an unsubstituted or substituted C1-C6 alkyl group, and the substituted C1-C6 alkyl group is the same or different, A halogeno group, a C3-C7 cycloalkyl group, a phenyl group (this phenyl group is substituted by a group selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group). A 5- or 6-membered aromatic heterocyclic group (the aromatic heterocyclic ring of this aromatic heterocyclic group is composed of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group. 1 to 3 groups may be substituted with a group selected from the group), a 4- to 7-membered aliphatic heterocyclic group (the aliphatic heterocyclic group of this aliphatic heterocyclic group is a halogeno group, C1-C6 alkyl) 1 to 3 groups may be substituted with a group selected from the group consisting of a group, a hydroxyl group and a C1-C6 alkoxy group 4- to 7-membered aliphatic heterocyclic group—CO group (this aliphatic heterocyclic group is a group selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group) 1 to 3 may be substituted), hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group, C3-C7 cycloalkyloxy group, phenyl C1-C6 alkoxy group (this phenyl C1 The phenyl group of the -C6 alkoxy group may be substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group), a phenoxy group ( The phenoxy group is a group selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group. May be substituted. ), Amino group, mono (C1-C6 alkyl) amino group, di (C1-C6 alkyl) amino group, C2-C6 alkanoylamino group, benzoylamino group (the benzoyl group of this benzoylamino group is a halogeno group, 1 to 3 groups may be substituted with a group selected from the group consisting of C1-C6 anolenoquinole group, hydroxyl group and C1-C6 alkoxy group), benzenoreamino group (the benzyl group of this benzylamino group is a halogeno group, C1 1 to 3 groups may be substituted with a group selected from the group consisting of a C6-anolequinole group, a hydroxyl group, and a C1-C6 alkoxy group.), C1-C6 alkylthio group, C1-C6 alkylsulfinyl group, C1- A C6 alkylsulfonyl group, a phenylthio group (the phenyl group of the phenylthio group is selected from the group consisting of a no, a logeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group). 1 to 3 groups may be substituted.), Phenylsulfinyl group (the phenylsulfinyl group is composed of a halogeno group, a C1-C6 alkanoleno group, a hydroxyl group, and a C1-C6 alkoxy group). 1 to 3 groups may be substituted with a group selected from the group), and a phenylsulfonyl group (the phenylsulfonyl group of this phenylsulfonyl group is a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group). 1 to 3 substituted with a group selected from the group consisting of groups! /, Or even! /) C1 to C6 alkynole groups substituted with 1 to 3 groups selected from the group consisting of Indicates.
(18— 1) 5又は 6員の芳香族複素環基とは、上記の 5又は 6員環の芳香族複素環 から形成される一価の基を示し、例えばピロリル基（1 ピロリル基、 2—ピロリル基又 は 3 ピロリル基を示す。）、フリル基（2 フリル基又は 3 フリル基を示す。）、チェ ニル基（2 チェニル基又は 3 チェ二ル基を示す。）、ピラゾリル基（1 ビラゾリノレ 基、 3—ピラゾリル基又は 4 ピラゾリル基を示す。）、イミダゾリル基（1 イミダゾリノレ 基、 2 イミダゾリル基又は 4 イミダゾリル基を示す。）、ォキサゾリル基（2 ォキサ ゾリル基、 4ーォキサゾリル基又は 5—ォキサゾリル基を示す。）、イソォキサゾリル基（ 3—イソォキサゾリル基、 4 イソォキサゾリル基又は 5—イソォキサゾリル基を示す。 ) 、チアゾリル基（2 チアゾリル基、 4 チアゾリル基又は 5 チアゾリル基を示す。）、 イソチアゾリル基（3—イソチアゾリル基、 4 イソチアゾリル基又は 5—イソチアゾリル 基を示す。）、ピリジル基（2 ピリジル基、 3 ピリジル基又は 4 ピリジル基を示す。 )、ピリダジニル基（3—ピリダジニル基、 4 ピリダジニル基又は 5—ピリダジニル基を 示す。）、ピリミジニル基（2 ピリミジニル基、 4 ピリミジニル基又は 5 ピリミジニル 基を示す。）、及びピラジュル基（2 ピラジュル基又は 3 ピラジュル基を示す）等を 挙げること力 Sでさる。 (18-1) The 5- or 6-membered aromatic heterocyclic group is a monovalent group formed from the above-mentioned 5- or 6-membered aromatic heterocyclic ring. For example, a pyrrolyl group (1 pyrrolyl group, 2 —Pyrrolyl group or 3 pyrrolyl group), furyl group (2 furyl group or 3 furyl group), phenyl group (2 phenyl group or 3 phenyl group), pyrazolyl group (1 Biazolinole group, 3-pyrazolyl group or 4-pyrazolyl group), imidazolyl group (1 imidazolino group, 2 imidazolyl group or 4 imidazolyl group), oxazolyl group (2 oxazolyl group, 4-oxazolyl group or 5-oxazolyl group) Group), isoxazolyl group (3-isoxazolyl group, 4 isoxazolyl group or 5-isoxazolyl group)), thiazolyl group (2 thiazolyl group, 4 thiazolyl group or 5 thiol Azolyl group), isothiazolyl group (3-isothiazolyl group, 4 isothiazolyl group or 5-isothiazolyl group), pyridyl group (2 pyridyl group, 3 pyridyl group or 4 pyridyl group is represented)), pyridazinyl group ( 3-pyridazinyl group, 4-pyridazinyl group or 5-pyridazinyl group Show. ), Pyrimidinyl groups (indicating 2-pyrimidinyl groups, 4-pyrimidinyl groups or 5-pyrimidinyl groups), pyrajul groups (indicating 2-pyrazuryl groups or 3-pyrazuryl groups) and the like.
(18— 2) 4〜7員の脂肪族複素環基とは、環の構成元素として、窒素原子、酸素原 子及び硫黄原子から選ばれるヘテロ原子を 1又は 2個含む、 4〜7員環の脂肪族複 素環から形成される 1価の基を示す。 4〜7員環の脂肪族複素環基としては、例えば ァゼチジュル基（ 1 ァゼチジュル基、 2 ァゼチジュル基又は 3 ァゼチジュル基 を示す。）、ォキセタニル基（2 ォキセタニル基又は 3 ォキセタニル基を示す。）、 チェタニル基（2 チェタニル基又は 3 チェタニル基を示す。）、ピロリジニル基（1 ピロリジニル基、 2 ピロリジニル基又は 3 ピロリジニル基を示す。）、テトラヒドロフ ラニル基（2 テトラヒドロフラニル基又は 3 テトラヒドロフラニル基を示す。）、テトラヒ ドロチォフエニル基（2 テトラヒドロチォフエニル基又は 3 テトラヒドロチォフエニル 基を示す。）、 1 , 1ージォキソーテトラヒドロー 1一え6—チォフエニル基 [2— (1 , 1— ジォキソ一テトラヒドロ一 l—λ 6 チォフエニル）基又は 3— (1 , 1—ジォキソ一テトラ ヒドロー 1一え6 チォフエニル)基を示す。 ]、ォキサゾリジニル基（2—ォキサゾリジ ニル基、 3—ォキサゾリジニル基、 4 ォキサゾリジニル基又は 5—ォキサゾリジニル 基を示す。）、ォキサゾリニル基（2 ォキサゾリニル基、 3 ォキサゾリニル基、 4ーォ キサゾリニル基又は 5 ォキサゾリ二ル基を示す。）、チアゾリジニル基（2 チアゾリ ジニル基、 3—チアゾリジニル基、 4 チアゾリジニル基又は 5—チアゾリジニル基を 示す。）、イミダゾリジニル基（1 イミダゾリジニル基、 2—イミダゾリジニル基又は 4 イミダゾリジニル基を示す。）、ピペリジニル基（1ーピペリジニル基、 2—ピペリジニル 基、 3 ピペリジニル基又は 4ーピペリジニル基を示す。）、テトラヒドロビラニル基（2 ーテトラヒドロビラニル基、 3—テトラヒドロビラニル基又は 4ーテトラヒドロビラ二ル基を 示す。）、テトラヒドロチォピラニル基（2 テトラヒドロチォピラニル基、 3 テトラヒドロ チォピラニル基又は 4ーテトラヒドロチォピラニル基を示す。）、ピペラジニル基（1ーピ ペラジニル基、 2 ピペラジニル基又は 3 ピペラジニル基を示す。）、モルホリニル 基（4 モルホリニル基、 2 モルホリニル基又は 3 モルホリニル基を示す。）、チォ モルホリニル基（4 チオモルホリニル基、 2 チオモルホリニル基又は 3 チォモノレ ホリニル基を示す。）、 [1 , 4]ジォキサニル基（2— [1 , 4]ジォキサニル基又は 3— [1 , 4]ジォキサニル基を示す。）、 [1 , 4]ォキサチアニル基（2— [1 , 4]ォキサチア二 ル基又は 3 [1 , 4]ォキサチア二ル基を示す。）、ホモピペリジニル基（1 ホモピぺ リジニル基、 2 ホモピペリジニル基、 3 ホモピペリジニル基又は 4 ホモピペリジニ ル基を示す。）、ォキセパニル基（2 ォキセパニル基、 3 ォキセパニル基又は 4 ォキセパニル基を示す。）、チェパニル基（2 チェパニル基、 3 チェパニル基又 は 4 チェパニル基を示す。）、 [1 , 4]ジァゼパニル基（1 [1 , 4]ジァゼパニル基、 2— [1 , 4]ジァゼパニル基又は 3— [1 , 4]ジァゼパニル基を示す。）、 [1 , 4]ォキサ ゼパニル基（4 [1 , 4]ォキサゼパニル基、 2— [1 , 4]ォキサゼパニル基又は 3— [1 , 4]ォキサゼパニル基を示す。）、及び [1 , 4]チアゼパニル基（4 [1 , 4]チアゼパ ニル基、 2— [1 , 4]チアゼパニル基又は 3— [1 , 4]チアゼパニル基を示す。）等を挙 げること力 Sでさる。 (18-2) A 4- to 7-membered aliphatic heterocyclic group is a 4- to 7-membered ring containing 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring constituent elements. Represents a monovalent group formed from an aliphatic complex ring. Examples of the 4- to 7-membered aliphatic heterocyclic group include azetidyl group (indicating 1-azetidyl group, 2-azetidyl group or 3-azetidyl group), oxetanyl group (indicating 2-oxetanyl group or 3-oxetanyl group), and chetanyl. Group (indicating 2 chetanyl group or 3 chetanyl group), pyrrolidinyl group (indicating 1 pyrrolidinyl group, 2 pyrrolidinyl group or 3 pyrrolidinyl group), tetrahydrofuranyl group (indicating 2 tetrahydrofuranyl group or 3 tetrahydrofuranyl group). ), Tetrahydrothienyl group (indicating 2 tetrahydrothiphenyl group or 3 tetrahydrothienyl group), 1,1-dioxotetrahydro 1-to- 6 -thiophenyl group [2- (1,1, -dioxo-one] tetrahydro one l-lambda 6 Chiofueniru) group or 3- (1, 1-Jiokiso one tetra Hidoro 1 one It shows the 6 Chiofueniru) group. ], Oxazolidinyl group (represents 2-oxazolidinyl group, 3-oxazolidinyl group, 4 oxazolidinyl group or 5-oxazolidinyl group), oxazolinyl group (2 oxazolinyl group, 3 oxazolinyl group, 4 oxazolinyl group or 5 oxazolinyl group or 5 oxazolinyl group Group), thiazolidinyl group (represents 2 thiazolidinyl group, 3-thiazolidinyl group, 4 thiazolidinyl group or 5-thiazolidinyl group), imidazolidinyl group (1 imidazolidinyl group, 2-imidazolidinyl group or 4 imidazolidinyl group. ), Piperidinyl group (represents 1-piperidinyl group, 2-piperidinyl group, 3-piperidinyl group or 4-piperidinyl group), tetrahydrobiranyl group (2-tetrahydrobiranyl group, 3-tetrahydrobiranyl group or 4-tetrahydroviranyl group) Indicates the group ), Tetrahydrothiopyranyl group (represents 2 tetrahydrothiopyranyl group, 3 tetrahydrothiopyranyl group or 4-tetrahydrothiopyranyl group), piperazinyl group (1-piperazinyl group, 2 piperazinyl group or 3 piperazinyl group) ), Morpholinyl group (represents 4 morpholinyl group, 2 morpholinyl group or 3 morpholinyl group), thiomorpholinyl group (4 thiomorpholinyl group, 2 thiomorpholinyl group or 3 thiomonoreylene) Indicates a holinyl group. ), [1, 4] dioxanyl group (2— [1,4] dioxanyl group or 3- [1,4] dioxanyl group), [1,4] oxanthanyl group (2 -— [1,4] oxanthia 2 or 3 [1, 4] oxathiadiyl group), homopiperidinyl group (1 homopiperidinyl group, 2 homopiperidinyl group, 3 homopiperidinyl group or 4 homopiperidinyl group), oxepanyl group (2 oxepanyl group) Group, 3 oxepanyl group or 4 oxepanyl group), chepanyl group (2 chepanyl group, 3 chepanyl group or 4 chepanyl group), [1,4] diazepanyl group (1 [1,4] diazepanyl group , 2- [1,4] diazepanyl group or 3- [1,4] diazepanyl group), [1,4] oxazepanyl group (4 [1,4] oxazepanyl group, 2- [1,4] An oxazepanyl group or a 3- [1,4] oxazepanyl group). And [1,4] thiazepanyl group (representing 4 [1,4] thiazepanyl group, 2- [1,4] thiazepanyl group or 3- [1,4] thiazepanyl group), etc. I'll do it.
(18— 3) 4〜7員の脂肪族複素環基 CO 基とは、上記の 4〜7員の脂肪族複素 環基とカルボニル基から形成される基を示す。  (18-3) 4- to 7-membered aliphatic heterocyclic group CO group refers to a group formed from the above 4- to 7-membered aliphatic heterocyclic group and a carbonyl group.
[0037] (18— 4) C3〜C7シクロアルキルォキシ基とは、上記の C3〜C7シクロアキル基か ら形成される C3〜C7シクロアキルォキシ基を示す。  (18-4) The C3 to C7 cycloalkyloxy group refers to a C3 to C7 cycloalkyloxy group formed from the above C3 to C7 cycloalkyl group.
[0038] (18— 5)フエニル C1〜C6アルコキシ基とは、フエ二ル基カ 個置換した C1〜C6ァ ルキルォキシ基を示し、例えばべンジルォキシ基、 2—フエニルエトキシ基、 1 フエ ニルエトキシ基、 3 フエニルプロポキシ基、 2 フエニルプロポキシ基、 4 フエ二ノレ —n—ブトキシ基、 5—フエ二ルー n—ペンチルォキシ基、 6—フエ二ルー n へキシ ノレォキシ基等を挙げることができる。  [0038] (18-5) phenyl C1-C6 alkoxy group refers to a C1-C6 alkyloxy group substituted with a phenyl group, for example, a benzyloxy group, a 2-phenylethoxy group, a 1-phenylethoxy group. 3 phenylpropoxy group, 2 phenylpropoxy group, 4 phenyl-n-butoxy group, 5-phenyl n-pentyloxy group, 6-phenyl n-hexyloxy group and the like.
[0039] (18— 6) C2〜C6アルカノィルァミノ基とは、炭素数；!〜 5の直鎖又は分枝鎖状の アルキル基とカルボニル基から形成されるアルカノィル基で置換されたアミノ基を示 し、例えばァセチルァミノ基、 n—プロピオニルァミノ基、 n ブチリルァミノ基、イソブ チリルァミノ基、 tert ブチリルァミノ基、 n—ペンタノィルァミノ基、（3—メチル） n ーブチリルァミノ基、 n へキサノィルァミノ基、（4、 4ージメチル） n ブチリルァミノ 基及び（5—メチル） n ペンタノィルァミノ基等を挙げることができる。  [0039] (18-6) A C2-C6 alkanoylamino group is an amino substituted with an alkanoyl group formed from a linear or branched alkyl group having carbon number; Groups such as acetylamino groups, n-propionylamino groups, n-butyrylamino groups, isobutyrylamino groups, tert-butyrylamino groups, n-pentanoylamino groups, (3-methyl) n-butyrylamino groups, n-hexanoylamino groups, Examples include (4,4-dimethyl) n butyrylamino group and (5-methyl) n pentanoylamino group.
(18— 7) C1〜C6アルキルスルフィエル基としては、例えばメチルスルフィエル基、 ェチノレスノレフィニノレ基、 n プロピノレスノレフィニノレ基、イソプロピノレスノレフィニノレ基、 n ーブチノレスノレフィニノレ基、 2—メチノレー n ブチノレスノレフィニノレ基、 tert ブチノレスノレ フィエル基、 n ペンチルスルフィエル基及び n へキシルスルフィエル基等が挙げら れる。 (18-7) C1-C6 alkyl sulfiel group, for example, methyl sulfiel group, Ethinolesno refininole group, n propino lesno refinino group, isopropino les no refinino group, n-butino les no refinino group, 2-methino ree n butino les no refinino group, tert butino les nore fiel Group, n pentyl sulfier group, n hexyl sulfier group and the like.
[0040] (19)フエニル C1 C6アルキル基とは、フエニル基が 1個置換した C1 C6アルキ ノレ基を示し、例えばべンジル基、 2 フエニルェチル基、 1 フエニルェチル基、 3— フエ二ノレ一 n プロピノレ基、 2 フエ二ノレ一 n プロピノレ基、 4 フエ二ノレ一 n ブチ ル基、 5—フエ二ノレ n ペンチル基及び 6—フエ二ノレ n へキシル基等を挙げる こと力 Sでさる。  [0040] (19) A phenyl C1 C6 alkyl group refers to a C1 C6 alkynol group in which one phenyl group is substituted. For example, a benzyl group, a 2-phenylethyl group, a 1-phenylethyl group, a 3-phenylenoyl-propynol group. Group, 2-phenolino-propynole group, 4-phenolino-butylyl group, 5-phenolinopentyl group, 6-phenolenohexyl group, etc.
[0041] (20) 5又は 6員の芳香族複素環基 C1 C6アルキル基とは、上記の 5又は 6員 環の芳香族複素環基で 1個置換された C1 C6アルキル基を示し、例えばピロリルメ チノレ基、フリルメチル基、チェニルメチル基、ピラゾリルメチル基、イミダゾリルメチル 基、ォキサゾリルメチル基、イソォキサゾリルメチル基、チアゾリルメチル基、イソチア ゾリルメチル基、ピリジルメチル基、ピリダジニルメチル基、ピリミジニルメチル基、ビラ ジニルメチル基、 2—（ピロリル）ェチル基、 2—（フリル）ェチル基、 2—（チェニル）ェ チル基、 2— (ビラゾリル）ェチル基、 2— (イミダゾリル）ェチル基、 2— (ォキサゾリル） ェチル基、 2—（イソォキサゾリル）ェチル基、 2—（チアゾリル）ェチル基、 2—（イソチ ァゾリル）ェチル基、 2— (ピリジル）ェチル基、 2— (ピリダジニル）ェチル基、 2— (ピリ ミジニル）ェチル基、 2 （ピラジュル）ェチル基、 3 （ピロリル）—n—プロピル基、 3 - (フリノレ） n プロピノレ基、 3 - (チェ二ノレ） n プロピノレ基、 3 - (ビラゾリル） n —プロピル基、 3— (イミダゾリル） n プロピル基、 3 - (ォキサゾリル） n プロピ ル基、 3—（イソォキサゾリル） n—プロピル基、 3—（チアゾリル） n—プロピル基、 3 - (イソチアゾリル）—n プロピル基、 3 - (ピリジル）—n プロピル基、 3— (ピリダ ジニル） n プロピル基、 3 - (ピリミジェル） n プロピル基、 3 - (ピラジュル） n—プロピル基、 4 （ピロリル） n ブチル基、 4 （フリノレ） n ブチル基、 4一 ( チェニル） n ブチル基、 4 （ビラゾリル） n ブチル基、 4 （イミダゾリノレ） n ブチル基、 4 （ォキサゾリル） n ブチル基、 4 （イソォキサゾリル） n ブチ ル基、 4 （チアゾリル） n ブチル基、 4 （イソチアゾリル） n ブチル基、 4 ピリジル） n ブチル基、 4— (ピリダジニル） n ブチル基、 4— (ピリミジニル）― n ブチル基、 4 （ピラジュル） n ブチル基、 5—（ピロリル） n ペンチル基、 5 （フリノレ） n—ペンチル基、 5—（チェニル） n—ペンチル基、 5—（ビラゾリル） n ペンチル基、 5—（イミダゾリル） n ペンチル基、 5—（ォキサゾリル） n ペン チル基、 5—（イソォキサゾリル） n ペンチル基、 5—（チアゾリル） n ペンチル 基、 5—（イソチアゾリル） n ペンチル基、 5—（ピリジノレ） n ペンチル基、 5— ( ピリダジニル）—n ペンチル基、 5— (ピリミジニル）—n ペンチル基、 5— (ピラジュ ノレ） n—ペンチル基、 6—（ピロリル） n へキシル基、 6—（フリノレ） n へキシル 基、 6—（チェニル）—n へキシル基、 6—（ビラゾリル）—n へキシル基、 6—（イミ ダゾリル） n へキシル基、 6—（ォキサゾリル） n へキシル基、 6—（イソォキサ ゾリル） n へキシル基、 6—（チアゾリル） n へキシル基、 6—（イソチアゾリル） —n へキシル基、 6— (ピリジル）—n へキシル基、 6— (ピリダジニル） n へキ シル基、 6— (ピリミジニル）—n へキシル基及び 6— (ピラジュル）—n へキシル基 を挙げること力 Sでさる。 [0041] (20) The 5- or 6-membered aromatic heterocyclic group C1 C6 alkyl group refers to a C1 C6 alkyl group substituted by one of the 5- or 6-membered aromatic heterocyclic group, for example, Pyrrolylmethylol group, furylmethyl group, chenylmethyl group, pyrazolylmethyl group, imidazolylmethyl group, oxazolylmethyl group, isoxazolylmethyl group, thiazolylmethyl group, isothiazolylmethyl group, pyridylmethyl group, pyridazinylmethyl Group, pyrimidinylmethyl group, birazinylmethyl group, 2- (pyrrolyl) ethyl group, 2- (furyl) ethyl group, 2- (chenyl) ethyl group, 2- (virazolyl) ethyl group, 2- (imidazolyl) ethyl group 2- (oxazolyl) ethyl group, 2- (isoxazolyl) ethyl group, 2- (thiazolyl) ethyl group, 2- (isothiolyl) ethyl group, 2- (pyridyl) Ethyl group, 2— (pyridazinyl) ethyl group, 2— (pyrimidinyl) ethyl group, 2 (pyrazuryl) ethyl group, 3 (pyrrolyl) —n-propyl group, 3- (furinole) n propinole group, 3- Ninole) n Propinole group, 3-(Byrazolyl) n — Propyl group, 3 — (Imidazolyl) n Propyl group, 3 – (Oxazolyl) n Propyl group, 3 — (Isoxazolyl) n-propyl group, 3 — (Thiazolyl ) N-propyl, 3- (isothiazolyl) -n propyl, 3- (pyridyl) -n propyl, 3- (pyridazinyl) n propyl, 3-(pyrimidyl) n propyl, 3-(pyrazur) n-propyl group, 4 (pyrrolyl) n butyl group, 4 (furinole) n butyl group, 4 1 (chenyl) n butyl group, 4 (virazolyl) n butyl group, 4 (imidazolinole) n butyl group, 4 (oxy) Zoriru) n-butyl group, 4 (Isookisazoriru) n butyl group, 4 (thiazolyl) n-butyl group, 4 (isothiazolyl) n-butyl group, 4 Pyridyl) n butyl group, 4- (pyridazinyl) n butyl group, 4- (pyrimidinyl)-n butyl group, 4 (pyrazuryl) n butyl group, 5- (pyrrolyl) n pentyl group, 5 (furinole) n-pentyl group 5— (Cenyl) n-pentyl group, 5— (Byrazolyl) n pentyl group, 5— (imidazolyl) n pentyl group, 5— (oxazolyl) n pentyl group, 5— (isoxazolyl) n pentyl group, 5— (Thiazolyl) n pentyl group, 5- (isothiazolyl) n pentyl group, 5- (pyridinole) n pentyl group, 5- (pyridazinyl) -n pentyl group, 5- (pyrimidinyl) -n pentyl group, 5- (pyrazinole) ) N-pentyl group, 6- (pyrrolyl) n hexyl group, 6- (Frinole) n hexyl group, 6- (Chenyl) -n hexyl group, 6- (Virazolyl) -n hexyl group, 6- (Imidazolyl) n hexyl group, 6- (oxazolyl) n hexyl group, 6- (isoxazolyl) n hexyl group, 6- (thiazolyl) n hexyl group, 6- (isothiazolyl) —n hexyl group 6- (pyridyl) -n hexyl group, 6- (pyridazinyl) n hexyl group, 6- (pyrimidinyl) -n hexyl group and 6- (pyrazuryl) -n hexyl group Monkey.
[0042] (21) 4〜7員環脂肪族複素環基ーじ1〜じ6ァルキル基とは、上記の 4〜7員環の 脂肪族複素環基で 1個置換された C1〜C6アルキル基を示す。  [0042] (21) 4- to 7-membered aliphatic heterocyclic group-1- to 6-alkyl group is a C1-C6 alkyl substituted with one of the above-mentioned 4- to 7-membered aliphatic heterocyclic group Indicates a group.
(22) 4〜7員の脂肪族複素環基ーじ〇ーじ1〜じ6ァルキル基とは、上記の 4〜7員 の脂肪族複素環 CO 基で 1個置換された上記の C 1〜C6アルキル基を示す。  (22) A 4- to 7-membered aliphatic heterocyclic group 1 to 6-alkyl group refers to the above C 1 substituted with one of the above 4 to 7-membered aliphatic heterocyclic CO groups. -C6 alkyl group is shown.
[0043] (23)ヒドロキシ C1〜C6アルキル基とは、水酸基で 1個置換された上記の C1〜C6 アルキル基を示す。  [0043] (23) Hydroxy C1-C6 alkyl group means the above C1-C6 alkyl group substituted by one hydroxyl group.
[0044] (24)フエノキシ C1〜C6アルキル基とは、フエノキシ基で 1個置換された上記の C1 〜C6アルキル基を示す。  [0044] (24) The phenoxy C1-C6 alkyl group refers to the above-mentioned C1-C6 alkyl group substituted by one phenoxy group.
(25)ァミノ C1〜C6ァノレキノレ基とは、ァミノ基で 1個置換された上記の C1〜C6アル キノレ基を示す。  (25) Amino C1-C6 anoleno group refers to the above C1-C6 alkino group substituted with one amino group.
[0045] (26) C2〜C6アルカノィルアミノー C1〜C6アルキル基とは、上記の C2〜C6アル カノィルァミノ基で 1個置換された上記の C1〜C6アルキル基を示す。  (26) The C2 to C6 alkanoylamino-C1 to C6 alkyl group refers to the above C1 to C6 alkyl group substituted with one of the above C2 to C6 alkanolamino groups.
[0046] (27)じ1〜じ6ァルキルチォじ1〜じ6ァルキル基とは、上記の C1〜C6アルキルチ ォ基で 1個置換された上記の C 1〜 C 6アルキル基を示す。 [0047] (28)じ1〜じ6ァルキルスルホニルじ1〜じ6ァルキル基とは、上記の C1〜C6アル キルスルホニル基で 1個置換された上記の C 1〜 C 6アルキル基を示す。 [0046] (27) 1 to 6 alkylthio 1 to 6 alkyl groups represent the above C 1 to C 6 alkyl groups substituted by one of the above C 1 to C 6 alkylthio groups. [0047] (28) 1 to 6 alkylsulfonyl refers to the above C 1 to C 6 alkyl group substituted by one of the above C1 to C6 alkylsulfonyl groups. .
[0048] 以下に本発明を詳細に説明する。  [0048] The present invention is described in detail below.
一般式 (I)における、
Figure imgf000019_0001
R2、環 A、 X及び Yについて説明する。 In general formula (I),
Figure imgf000019_0001
R 2 , rings A, X and Y will be described.
下記の一般式 (I) R  The following general formula (I) R
[0049] [化 3]  [0049] [Chemical 3]
Figure imgf000019_0002
Figure imgf000019_0002
[0050] における、 R1は、水素原子又は C1〜C6アルキル基を示し、水素原子又は C1〜C4 アルキル基が好ましい。 In [0050], R 1 represents a hydrogen atom or a C1-C6 alkyl group, preferably a hydrogen atom or a C1-C4 alkyl group.
[0051] R2は、置換基を有していてもよい C1〜C6アルキル基又は C3〜C7シクロアルキル 基を示す。 [0051] R 2 represents a C1-C6 alkyl group or a C3-C7 cycloalkyl group which may have a substituent.
[0052] 環 Aは、ベンゼン環、或いは、 5又は 6員の芳香族複素環を示し、ベンゼン環、フラ ン環、チォフェン環、ピロール環、ピラゾール環、ォキサゾール環、チアゾール環、ピ リジン環、ピリダジン環、ピリミジン環及びピラジン環が好ましい。  [0052] Ring A represents a benzene ring or a 5- or 6-membered aromatic heterocycle, and is a benzene ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an oxazole ring, a thiazole ring, a pyridine ring, Pyridazine ring, pyrimidine ring and pyrazine ring are preferred.
[0053] Xは、水素原子であるか、或いは、同一又は異なって、ハロゲノ基、 C1〜C6アルキ ル基、ハロゲノ C1〜C6アルキル基、 C1〜C6アルコキシ C1〜C6アルキル基、水酸 基、 C1〜C6アルコキシ基、ハロゲノ C1〜C6アルコキシ基、 C1〜C6ァノレコキシ C1 〜C6アルコキシ基、カルボキシ基、 C1〜C6アルコキシカルボニル基、シァノ基、力 ノレバモイル基、 N—モノ（C1〜C6アルキノレ）力ルバモイル基、 N, N—ジ（C1〜C6ァ ルキル）力ルバモイル基、アミノ基、モノ（C1〜C6アルキル）アミノ基、ジ（C1〜C6ァ ルキル）アミノ基、 C1〜C6アルキルチオ基、 C1〜C6アルキルスルホニル基及びニト 口基からなる群より選ばれる 1〜3個の基を示し、 [0053] X is a hydrogen atom, or the same or different, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group, C1-C6 anorecoxy C1-C6 alkoxy group, carboxy group, C1-C6 alkoxycarbonyl group, cyano group, force noveramoyl group, N-mono (C1-C6 alkynole) force Rubamoyl group, N, N-di (C1-C6 alkyl) force rubermoyl group, amino group, mono (C1-C6 alkyl) amino group, di (C1-C6 alkyl group) Alkyl) an amino group, a C1-C6 alkylthio group, a C1-C6 alkylsulfonyl group, and a group selected from the group consisting of a nitro group and 1-3 groups;
Xは、水素原子であるか、或いは、同一又は異なって、ハロゲノ基、 C1〜C6アルキ ル基、ハロゲノ C1〜C6アルキル基、水酸基、 C1〜C6アルコキシ基、ハロゲノ C；!〜 C6アルコキシ基、カルボキシ基、 C1〜C6アルコキシカルボニル基、シァノ基からな る群より選ばれる 1〜3個の基が好ましい。  X is a hydrogen atom, or the same or different, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a hydroxyl group, a C1-C6 alkoxy group, a halogeno C;! -C6 alkoxy group, 1 to 3 groups selected from the group consisting of a carboxy group, a C1-C6 alkoxycarbonyl group and a cyano group are preferred.
[0054] Yは、下記の式（a)〜 又は（V)  [0054] Y represents the following formula (a) to (V)
[0055] [化 4]  [0055] [Chemical 4]
Figure imgf000020_0001
Figure imgf000020_0001
(g) 、 (h) 、 ( i ) 、 (j)  (g), (h), (i), (j)
R R
八 ノ「R Hachino R
(CH2) q (CH 2 ) q
(v)  (v)
(式中、 R3a、 R3b、 R3c、 R3d、 R3e、 R3f、 R3g及び R3vは、同一又は異なって、水素原子 又は C1〜C6アルキル基を示し、 (Wherein R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3v are the same or different and represent a hydrogen atom or a C1-C6 alkyl group,
R4a、 R5a、 R4b、 R5b、 R4c、 R5c、 R4d、 R5d、 R4h、 R5h、 R4i、 R5i、 R4j及び R5jは、同一又は 異なって、水素原子、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C1〜C6 アルコキシ C1〜C6アルキル基、C3〜C7シクロアルキル基又は C3〜C7シクロアル キル C1〜C6アルキル基を示す力、、又は、 R 4a , R 5a , R 4b , R 5b , R 4c , R 5c , R 4d , R 5d , R 4h , R 5h , R 4i , R 5i , R 4j and R 5j are the same or different and are hydrogen atoms , A C1-C6 alkylenole group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkyl group or a C3-C7 cycloalkyl C1-C6 alkyl group, or
R4aと R5a、 R4bと R5b、 R4cと R5c、 R4dと R5d、 R4hと R5h、 R4iと R5i、及び R4jと R5jは、同一又 は異なって、 2つの基が結合する窒素原子と一体化して 4〜7員の含窒素脂肪族複 素環 (この含窒素脂肪族複素環は、ハロゲノ基、 C1〜C6アルキル基、ハロゲノ Cl〜 C6ァノレキノレ基、 C1〜C6アルコキシ C1〜C6アルキル基、水酸基、 C1〜C6アルコ キシ基、ハロゲノ C1〜C6アルコキシ基及び C1〜C6アルコキシ C1〜C6アルコキシ 基からなる群より選ばれる基で 1〜3個置換されてもよい。）を形成してもよいことを示 し、 R 4a and R 5a , R 4b and R 5b , R 4c and R 5c , R 4d and R 5d , R 4h and R 5h , R 4i and R 5i , and R 4j and R 5j are the same or Are different from each other, and are integrated with a nitrogen atom to which two groups are bonded to a 4- to 7-membered nitrogen-containing aliphatic heterocyclic ring (this nitrogen-containing aliphatic heterocyclic ring is a halogeno group, a C1-C6 alkyl group, a halogeno Cl- 1 to 3 groups selected from the group consisting of C6 alkenoquinole group, C1 to C6 alkoxy C1 to C6 alkyl group, hydroxyl group, C1 to C6 alkoxy group, halogeno C1 to C6 alkoxy group and C1 to C6 alkoxy C1 to C6 alkoxy group Each may be substituted.)
R4e、 R4f及び R4gは、同一又は異なって、水素原子、 C1〜C6アルキル基、ハロゲノ C ；!〜 C6ァノレキノレ基、 C1〜C6アルコキシ C1〜C6アルキル基、 C3〜C7シクロアルキ ル基、 C 3〜 C 7シクロアルキル C；!〜 C 6アルキル基又はフエニル C；!〜 C 6アルキノレ 基（このフエニル C1〜C6アルキル基のフエニル基は、ハロゲノ基、 C1〜C6ァノレキノレ 基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換され ていてもよい。）を示し、 R 4e , R 4f and R 4g are the same or different and are a hydrogen atom, a C1-C6 alkyl group, a halogeno C;! -C6 alkanoleno group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkyl group, C 3 to C 7 cycloalkyl C;! To C 6 alkyl group or phenyl C;! To C 6 alkynole group (the phenyl group of this phenyl C1 to C6 alkyl group is a halogeno group, a C1 to C6 alkenyl group, a hydroxyl group and C1 1 to 3 groups may be substituted with a group selected from the group consisting of -C6 alkoxy groups).
R6a、 R6b、 R7a、 R7b、 R8a、 R8b、 R9a、 R9b、 R10b及び Rubは、同一又は異なって、水素 原子、ハロゲノ基、 C 1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C 1〜C6ァ ルコキシ C1〜C6アルキル基、水酸基、 C1〜C6アルコキシ基、ハロゲノ C1〜C6ァ ルコキシ基又は C1〜C6アルコキシ C1〜C6アルコキシ基を示し、 R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10b and R ub are the same or different and represent a hydrogen atom, a halogeno group, a C1-C6 anorequinole group, a halogeno group. C1-C6 alkyl group, C1-C6 alkyloxy C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy C1-C6 alkoxy group,
„ 12c „ 12d „ 12e „ 12f „ 12g „ 12h „ 12i „ 12j „ 12v „ 13c „ 13d „ 13e „ 13f „ 13g „ 1 „12c„ 12d „12e„ 12f „12g„ 12h „12i„ 12j „12v„ 13c „13d„ 13e „13f„ 13g „1
J 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 3h、 R13l、 R13j、 R13v、 R14c、 R14d、 R14e、 R14f、 R14\ R14h、 R14l、 R14j及び R14vは、同一 又は異なって、水素原子、ハロゲノ基、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アル キル基、 C1〜C6アルコキシ C1〜C6アルキル基、水酸基、 C1〜C6アルコキシ基、 ハロゲノ C1〜C6アルコキシ基又は C1〜C6アルコキシ C1〜C6アルコキシ基を示し k、 1、 m、 n、 o及び pは、それぞれ、 0、 1又は 2を示し、 qは、 1又は 2を示し、 J, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_ 3h, R 13l, R 13j, R 13v, R 14c, R 14d, R 14e, R 14f , R 14 \ R 14h , R 14l , R 14j and R 14v are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 alkenoquinole group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 An alkyl group, a hydroxyl group, a C1-C6 alkoxy group, a halogeno C1-C6 alkoxy group or a C1-C6 alkoxy C1-C6 alkoxy group, and k, 1, m, n, o and p are 0, 1 or 2, respectively. Q represents 1 or 2,
Vは、モルホリノ基を示す。 V represents a morpholino group.
上記式 (a)〜 及び (V)中の、 R3a、 R3b、 R3c、 R3d、 R3e、 R3f、 R 、 R3v、 R4a、 R4b、
Figure imgf000021_0001
In the above formulas (a) to (V), R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R, R 3v , R 4a , R 4b ,
Figure imgf000021_0001
7a ヒ ^ eb ^ 9a ^ 9b ^ 10b ^ lib ^ 12c ^ 12d ^ 12e ^ 12f ^ 12g ^ 12h ^ 12i ^ 7a hi ^ eb ^ 9a ^ 9b ^ 10b ^ lib ^ 12c ^ 12d ^ 12e ^ 12f ^ 12g ^ 12h ^ 12i ^
12i ^ 12v ^ 13c ^ 13d ^ 13e ^ 13f ^ 13g ^ 13h ^ 13i ^ 13i ^ 13v ^ 14c ^ 14d ^ 14e ^ 14f 、 R14g、 R14h、 R14i、 R14j、 R14v、 k、 1、 m、 n、 o、 p及び qの好ましい態様について説明 する。 12i ^ 12v ^ 13c ^ 13d ^ 13e ^ 13f ^ 13g ^ 13h ^ 13i ^ 13i ^ 13v ^ 14c ^ 14d ^ 14e ^ 14f Preferred embodiments of R 14g , R 14h , R 14i , R 14j , R 14v , k, 1, m, n, o, p and q will be described.
[0058] R3a、 R3b、 R3\ R3d、 R3 R3f、 R3g及び R3vは、同一又は異なって、水素原子、メチ ル基、ェチル基、 n—プロピル基、イソプロピル基及び n—ブチル基が好ましく、 同一又は異なって、水素原子及びメチル基がより好まし!/、。 [0058] R 3a , R 3b , R 3 \ R 3d , R 3 R 3f , R 3g and R 3v are the same or different and are a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group and n-Butyl group is preferred, the same or different, hydrogen atom and methyl group are more preferred! / ,.
[0059] R4a、 R5a、 R4b、 R5b、 R4\ R5 R4d、 R5d、 R4h、 R5h、 R4i、 R5i、 R4j及び R5jは、下記の（ 1)及び（2) [0059] R 4a, R 5a , R 4b, R 5b, R 4 \ R 5 R 4d, R 5d, R 4h, R 5h, R 4i, R 5i, R 4j and R 5j are the following (1) And (2)
(1)同一又は異なって、水素原子、 C1〜C4ァノレキノレ基、ハロゲノ C1〜C4アルキル 基、 C1〜C4アルコキシ C1〜C4アルキル基、 C3〜C5シクロアルキル基及び C3〜 C5シクロアルキル C1〜C4アルキル基から選ばれる基；  (1) Same or different, hydrogen atom, C1-C4 anolenoquinole group, halogeno C1-C4 alkyl group, C1-C4 alkoxy C1-C4 alkyl group, C3-C5 cycloalkyl group and C3-C5 cycloalkyl C1-C4 alkyl A group selected from the group;
(2) R4aと R5a、 R4bと R5b、 R4cと R5c、 R4dと R5d、 R4hと R5h、 R4iと R5i、及び R4jと R5jとが、 同一又は異なって、 2つの基が結合する窒素原子と一体化して 4〜7員の含窒素脂 肪族複素環 (この含窒素脂肪族複素環は、ハロゲノ基、 C1〜C6アルキル基、ハロゲ ノ C1〜C6アルキル基、 C1〜C6アルコキシ C1〜C6アルキル基、水酸基、 C1〜C6 アルコキシ基、ハロゲノ C1〜C6アルコキシ基及び C1〜C6アルコキシ C1〜C6アル コキシ基からなる群より選ばれる基で 1〜3個置換されてもよい。）を形成する； が好ましぐ (2) R 4a and R 5a , R 4b and R 5b , R 4c and R 5c , R 4d and R 5d , R 4h and R 5h , R 4i and R 5i , and R 4j and R 5j are the same or In contrast, a 4- to 7-membered nitrogen-containing aliphatic heterocycle integrated with a nitrogen atom to which two groups are bonded (this nitrogen-containing aliphatic heterocycle is a halogeno group, a C1-C6 alkyl group, a halogeno C1- A group selected from the group consisting of C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group and C1-C6 alkoxy C1-C6 alkoxy group 1-3 May be substituted.) Is preferred
下記の（3)及び (4)  (3) and (4) below
(3)同一又は異なって、水素原子、メチル基及びェチル基；  (3) the same or different, a hydrogen atom, a methyl group and an ethyl group;
(4) R4aと R5a、 R4bと R5b、 R4cと R5c、 R4dと R5d、 R4hと R5h、 R4iと R5i、及び R4jと R5jとが、 同一又は異なって、 2つの基が結合する窒素原子と一体化してピロリジン環又はピぺ リジン環（このピロリジン環及びピぺリジン環は、ハロゲノ基、 C1〜C6アルキル基、ハ ロゲノ C1〜C6アルキル基、 C 1〜C6アルコキシ C1〜C6アルキル基、水酸基、 C1 〜 C 6アルコキシ基、ハロゲノ C1〜C6アルコキシ基及び C1〜C6アルコキシ C 1〜 C 6アルコキシ基からなる群より選ばれる基で 1〜3個置換されてもよい。）を形成する； がより好ましい。 (4) R 4a and R 5a , R 4b and R 5b , R 4c and R 5c , R 4d and R 5d , R 4h and R 5h , R 4i and R 5i , and R 4j and R 5j are the same or In contrast, a pyrrolidine ring or a piperidine ring combined with a nitrogen atom to which two groups are bonded (the pyrrolidine ring and the piperidine ring are a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group and C1-C6 alkoxy group selected from the group consisting of C1-C6 alkoxy group 1-3 Is more preferred.
[0060] R4e、 R4f及び R4gは、同一又は異なって、水素原子、 C1〜C4アルキル基、ハロゲノ C1〜C4アルキル基、 C1〜C4アルコキシ C1〜C4アルキル基、 C3〜C5シクロアノレ キル基、 C3〜C5シクロアルキル C 1〜 C4アルキル基及びフエニル C；!〜 C 4アルキ ノレ基（このフエニル C1〜C4アルキル基のフエニル基は、ハロゲノ基、 C1〜C4アルキ ル基、水酸基及び C1〜C4アルコキシ基からなる群より選ばれる基で 1〜3個置換さ れていてもよい。）が好ましい。 [0060] R 4e , R 4f and R 4g are the same or different and each represents a hydrogen atom, a C1-C4 alkyl group, a halogeno C1-C4 alkyl group, a C1-C4 alkoxy C1-C4 alkyl group, a C3-C5 cycloanol. Kill group, C3-C5 cycloalkyl C1-C4 alkyl group and phenyl C;! -C4 alkynol group (the phenyl group of this phenyl C1-C4 alkyl group is a halogeno group, C1-C4 alkyl group, hydroxyl group and 1 to 3 groups may be substituted with a group selected from the group consisting of C1 to C4 alkoxy groups).
[0061] R6a、 R6b、 R7a、 R7b、 R8a、 R8b、 R9a、 R9b、 R10b及び Rubは、同一又は異なって、水素 原子、ハロゲノ基、 C1〜C4ァノレキノレ基、ハロゲノ C1〜C4アルキル基、 C1〜C4ァ ルコキシ C1〜C4アルキル基、水酸基、 C1〜C4アルコキシ基、ハロゲノ C1〜C4ァ ルコキシ基及び C1〜C4アルコキシ C1〜C4アルコキシ基が好ましい。 [0061] R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10b, and R ub are the same or different and represent a hydrogen atom, a halogeno group, or a C1-C4 anolenoquine group A halogeno C1-C4 alkyl group, a C1-C4 alkoxy group, a C1-C4 alkyl group, a hydroxyl group, a C1-C4 alkoxy group, a halogeno C1-C4 alkoxy group, and a C1-C4 alkoxy C1-C4 alkoxy group are preferred.
p 12c 12 e p l2f p l2g 121ι 121 12 ^12 p 13 p l3d π 13θ p l3f p l3g p 12c 12 e p l2f p l2g 121ι 121 12 ^ 12 p 13 p l3d π 13θ p l3f p l3g
R13h、 R13l、 R13j、 R13v、 R14c、 R14d、 R14e、 R14f、 R14g、 R14h、 R14l、 R14j及び R14vは、同 一又は異なって、水素原子、ハロゲノ基、 C1〜C4ァノレキノレ基、ハロゲノ C1〜C4ァ ルキノレ基、 C1〜C4アルコキシ C1〜C4アルキル基、水酸基、 C1〜C4アルコキシ基 、ハロゲノ C1〜C4アルコキシ基及び C1〜C4アルコキシ C1〜C4アルコキシ基が好 ましい。 R 13h, R 13l, R 13j , R 13v, R 14c, R 14d, R 14e, R 14f, R 14g, R 14h, R 14l, R 14j and R 14v are the same or different and each represents a hydrogen atom, a halogeno Groups, C1-C4 alkanoleno groups, halogeno C1-C4 alkynole groups, C1-C4 alkoxy C1-C4 alkyl groups, hydroxyl groups, C1-C4 alkoxy groups, halogeno C1-C4 alkoxy groups and C1-C4 alkoxy C1-C4 alkoxy groups Is preferred.
[0063] k、 1、 m、 n、 o及び pは、それぞれ、 0又は 1が好ましぐ 0がより好ましい。 qは、 1が 好ましい。  [0063] k, 1, m, n, o and p are each preferably 0 or 1, more preferably 0. q is preferably 1.
[0064] R2は、置換基を有していてもよい C1〜C6アルキル基及び C3〜C7シクロアルキル 基が好ましい。 [0064] R 2 is preferably a C1-C6 alkyl group and a C3-C7 cycloalkyl group which may have a substituent.
置換基を有していてもよい C1〜C6アルキル基としては、 C1〜C6ァノレキノレ基、及 び、下記のハロゲノ基、 C3〜C7シクロアルキル基、フエニル基（このフエニル基は、 ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6アルコキシ基からなる群より 選ばれる基で 1〜3個置換されていてもよい。）、 5又は 6員の芳香族複素環基 (この 芳香族複素環基の芳香族複素環は、、ノ、ロゲノ基、 C1〜C6アルキル基、水酸基及 び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。 )、 4〜7員の脂肪族複素環基 (この脂肪族複素環基の脂肪族複素環は、、ハロゲノ 基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる 基で 1〜3個置換されていてもよい。）、 4〜7員の脂肪族複素環基 CO 基 (この 脂肪族複素環基は、ハロゲノ基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコ キシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、水酸基、 Cl〜 C6アルコキシ基、ハロゲノ C1〜C6アルコキシ基、 C3〜C7シクロアルキルォキシ基 、フエニル C；!〜 C6アルコキシ基（このフエニル C；!〜 C6アルコキシ基のフエ二ル基は 、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6アルコキシ基からなる群より 選ばれる基で 1〜3個置換されていてもよい。）、フエノキシ基（このフエノキシ基は、ハ ロゲノ基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選 ばれる基で 1〜3個置換されていてもよい。）、アミノ基、モノ（C1〜C6アルキル）アミ ノ基、ジ（C1〜C6アルキル）アミノ基、 C2〜C6アルカノィルァミノ基、ベンゾィルアミ ノ基（このべンゾィルァミノ基のベンゾィル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水 酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換されていて もよい。）、ベンジルァミノ基（このベンジルァミノ基のベンジル基は、ハロゲノ基、 C1 〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1 〜3個置換されていてもよい。）、 C；!〜 C6アルキルチオ基、 C1〜C6アルキルスルフ ィニル基、 C1〜C6アルキルスルホニル基、フエ二ルチオ基（このフエ二ルチオ基のフ ェニル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6アルコキシ基か らなる群より選ばれる基で 1〜3個置換されていてもよい。）、フエニルスルフィニル基（ このフエニルスルフィニル基のフエニル基は、ハロゲノ基、 C1〜C6アルキル基、水酸 基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換されていても よい。）、及びフエニルスルホニル基（このフエニルスルホニル基のフエニル基は、ハロ ゲノ基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ば れる基で 1〜3個置換されていてもよい。 )；からなる群より選ばれる基で 1〜3個置換 された C1〜C6アルキル基が好ましい。 Examples of the optionally substituted C1-C6 alkyl group include C1-C6 anolenoquinole group, and the following halogeno group, C3-C7 cycloalkyl group, phenyl group (this phenyl group is a halogeno group, C1 1 to 3 groups may be substituted with a group selected from the group consisting of ˜C6 anolenoquinole group, hydroxyl group and C1 to C6 alkoxy group), 5- or 6-membered aromatic heterocyclic group (this aromatic heterocyclic group) 1 to 3 of the aromatic heterocycles may be substituted with a group selected from the group consisting of a no, a logeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group. 7-membered aliphatic heterocyclic group (The aliphatic heterocyclic ring of this aliphatic heterocyclic group is a group selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group. 4 to 7-membered aliphatic heterocyclic group CO group (this aliphatic group may be substituted) Heterocyclic group, a halogeno group, C1 -C6 alkyl group, a hydroxyl group and C1 -C6 alkoxy 1 to 3 groups may be substituted with a group selected from the group consisting of xy groups. ), Hydroxyl group, Cl to C6 alkoxy group, halogeno C1 to C6 alkoxy group, C3 to C7 cycloalkyloxy group, phenyl C;! To C6 alkoxy group (the phenyl group of this phenyl C;! To C6 alkoxy group is , A halogeno group, a C1 to C6 alkenoquinole group, a hydroxyl group and a group selected from the group consisting of a C1 to C6 alkoxy group, which may be substituted by 1 to 3 groups, a phenoxy group (this phenoxy group is a halogeno group, 1 to 3 groups may be substituted with a group selected from the group consisting of C1-C6 alkyl group, hydroxyl group and C1-C6 alkoxy group.), Amino group, mono (C1-C6 alkyl) amino group, di ( C1-C6 alkyl) amino group, C2-C6 alkanoylamino group, benzoylamino group (the benzoyl group of this benzoylamino group is composed of a halogeno group, a C1-C6 anorequinole group, a hydroxyl group, and a C1-C6 alkoxy group. group A benzylamino group (the benzyl group of the benzylamino group may be selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group). 1 to 3 groups may be substituted.), C;! To C6 alkylthio group, C1 to C6 alkylsulfinyl group, C1 to C6 alkylsulfonyl group, phenylthio group (the phenylthio group) The phenyl group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkenyl group, a hydroxyl group and a C1-C6 alkoxy group), a phenylsulfinyl group (this phenyl group). The phenyl group of the sulfinyl group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group.), And phenyls A sulfonyl group (the phenyl group of this phenylsulfonyl group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group). A C1-C6 alkyl group substituted with 1 to 3 groups selected from the group consisting of;
R2は、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C3〜C7シクロアルキ ル C 1〜 C 6アルキル基、フエニル C；!〜 C 6アルキル基（このフエニル C；!〜 C 6アルキ ル基のフエニル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6アルコ キシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、 5又は 6員の芳 香族複素環基 C1〜C6アルキル基 (この芳香族複素環基の芳香族複素環は、ノ、 ロゲノ基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選 ばれる基で 1〜3個置換されていてもよい。）、 4〜7員の脂肪族複素環基 C1〜C6 アルキル基 (この脂肪族複素環基の脂肪族複素環は、ハロゲノ基、 C1〜C6アルキ ル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換さ れていてもよい。）、 4〜7員の脂肪族複素環基 CO— C1〜C6アルキル基 (この脂 肪族複素環基は、ハロゲノ基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキ シ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、ヒドロキシ C1〜C 6ァノレキノレ基、 C1〜C6アルコキシ C1〜C6アルキル基、フエノキシ C1〜C6アルキ ル基（このフエノキシ基は、ハロゲノ基、 C1〜C6アルキル基、水酸基及び C1〜C6ァ ルコキシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、ァミノ Cl〜 C6ァノレキノレ基、 C2〜C6アルカノィルアミノー C1〜C6アルキル基、 C1〜C6アルキ ノレチォ C1〜C6アルキル基、 C1〜C6アルキルスルホニル C1〜C6アルキル基、及 び C3〜C7シクロアルキル基がより好まし!/、。 R 2 is a C1 to C6 alkylenole group, a halogeno C1 to C6 alkyl group, a C3 to C7 cycloalkyl C1 to C6 alkyl group, a phenyl C;! To C6 alkyl group (this phenyl C;! To C6 alkyl) The phenyl group of the group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkenyl group, a hydroxyl group, and a C1-C6 alkoxy group. Aromatic heterocyclic group C1-C6 alkyl group (The aromatic heterocyclic ring of this aromatic heterocyclic group is selected from the group consisting of a group consisting of a no, a logeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group. It may be substituted with 1 to 3 groups. ), A 4- to 7-membered aliphatic heterocyclic group C1-C6 alkyl group (the aliphatic heterocyclic ring of this aliphatic heterocyclic group comprises a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group) 1 to 3 groups may be substituted with a group selected from the group), a 4- to 7-membered aliphatic heterocyclic group CO—C1-C6 alkyl group (this aliphatic heterocyclic group is a halogeno group, 1 to 3 groups may be substituted with a group selected from the group consisting of a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group.), A hydroxy C1-C6 alkanoleno group, a C1-C6 alkoxy C1-C6 An alkyl group, a phenoxy C1-C6 alkyl group (this phenoxy group may be substituted by a group selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkyl group, Good)), Amino Cl to C6 Anolequinole group, C2 to C6 Alkanoylamino- C1 to C6 Al More preferred are a kill group, a C1-C6 alkinoreio C1-C6 alkyl group, a C1-C6 alkylsulfonyl C1-C6 alkyl group, and a C3-C7 cycloalkyl group! /.
R2は、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C3〜C7シクロアルキ ノレ C 1〜 C 6アルキル基、フエニル C；!〜 C 6アルキル基（このフエニル C；!〜 C 6アルキ ル基のフエニル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6アルコ キシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、 4〜7員の脂肪 族複素環基 CO— C1〜C6アルキル基 (この脂肪族複素環基は、ハロゲノ基、 C1 〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1 〜3個置換されていてもよい。）、 C；!〜 C6アルキルチオ C1〜C6アルキル基及び C3 〜C7シクロアルキル基がさらに好ましい。 R 2 is a C1 to C6 alkylenole group, a halogeno C1 to C6 alkyl group, a C3 to C7 cycloalkylene C1 to C6 alkyl group, a phenyl C;! To C6 alkyl group (this phenyl C;! To C6 alkyl) The phenyl group in the group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkenoquinole group, a hydroxyl group, and a C1-C6 alkoxy group.), A 4- to 7-membered fat Aromatic heterocyclic group CO—C1-C6 alkyl group (This aliphatic heterocyclic group is substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group. C;! To C6 alkylthio C1 to C6 alkyl groups and C3 to C7 cycloalkyl groups are more preferred.
さらにより好ましい R2としては、 C1〜C6ァノレキノレ基、フルォロ C1〜C6アルキル基 、 C3〜C7シクロアルキルメチル基、ベンジル基（このベンジル基は、ハロゲノ基、 C1 〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1 〜3個置換されていてもよい。）メチルチオ C1〜C6アルキル基及び C3〜C7シクロア ルキル基が挙げられる。 More preferable R 2 includes C1-C6 anolenoquinole group, fluoro C1-C6 alkyl group, C3-C7 cycloalkylmethyl group, benzyl group (this benzyl group is a halogeno group, C1-C6 alkyl group, hydroxyl group and C1- 1 to 3 groups may be substituted with a group selected from the group consisting of C6 alkoxy groups.) Examples include methylthio C1-C6 alkyl groups and C3-C7 cycloalkyl groups.
なおさらに好ましい R2としては、メチル基、ェチル基、 n プロピル基、イソプロピノレ 基、 n ブチル基、イソブチル基、 tert ブチル基、 n ペンチル基、 3—メチルー n ブチル基、 n へプチル基、 4ーメチルー n—ペンチル基、 3—フルオロー n—プロ ピノレ基、 4—フルオロー n ブチル基、 4—フルオロー 3—メチル n ブチル基、 5 —フルオロー n ペンチル基、 6—フルオロー n へキシル基、シクロプロピルメチル 基、シクロブチルメチル基、シクロペンチルメチル基、シクロへキシルメチル基、ベン ジル基（このベンジル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6 アルコキシ基からなる群より選ばれる基で 1〜3個置換されてもよい。）、シクロプロピ ル基、シクロブチル基、シクロペンチル基及びシクロへキシル基が挙げられる。 Still more preferable R 2 includes methyl group, ethyl group, n propyl group, isopropinole group, n butyl group, isobutyl group, tert butyl group, n pentyl group, 3-methyl-n butyl group, n heptyl group, 4 -Methyl-n-pentyl group, 3-fluoro-n-pro Pinole group, 4-fluoro-n-butyl group, 4-fluoro-3-methyl-n-butyl group, 5-fluoro-n-pentyl group, 6-fluoro-n-hexyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclo A hexylmethyl group, a benzyl group (this benzyl group may be substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1 to C6 alkenyl group, a hydroxyl group and a C1 to C6 alkoxy group), cyclopropyl. Group, cyclobutyl group, cyclopentyl group and cyclohexyl group.
なおさらにより好ましい R2としては、 3—フルオロー n プロピル基、 4—フルオロー n ブチル基、 4 フルオロー 3—メチルー n ブチル基、 5—フルオロー n—ペンチノレ 基、 6—フルオロー n へキシル基、シクロプロピルメチル基、シクロブチルメチル基、 シクロペンチルメチル基、ベンジル基（このベンジル基は、ハロゲノ基、 C1〜C6ァノレ キル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換 されてもよい。）、メチルチオェチル基、メチルチオプロピル基、シクロプロピル基、シ クロブチル基、シクロペンチル基及びシクロへキシル基が挙げられる。 Even more preferred R 2 includes 3-fluoro-n-propyl, 4-fluoro-n-butyl, 4-fluoro-3-methyl-n-butyl, 5-fluoro-n-pentynol, 6-fluoro-n-hexyl, cyclopropylmethyl Group, cyclobutylmethyl group, cyclopentylmethyl group, benzyl group (this benzyl group is substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkylene group, a hydroxyl group and a C1-C6 alkoxy group) And a methylthioethyl group, a methylthiopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
[0067] 一般式 (I)中の R1は、水素原子、メチル基及びェチル基が好ましぐ水素原子がよ り好ましい。 [0067] R 1 in the general formula (I) is more preferably a hydrogen atom, preferably a hydrogen atom, a methyl group or an ethyl group.
[0068] 一般式 (I)中の環 Aは、ベンゼン環、フラン環、チォフェン環、ピロール環、ピリジン 環、ピリダジン環、ピリミジン環及びピラジン環が好ましぐ  [0068] Ring A in general formula (I) is preferably a benzene ring, furan ring, thiophene ring, pyrrole ring, pyridine ring, pyridazine ring, pyrimidine ring or pyrazine ring.
ベンゼン環がより好ましぐ 1 , 4 フエ二レン基であるものが特に好ましい。  Particularly preferred is a 1,4-phenylene group where the benzene ring is more preferred.
[0069] 一般式（I)中の Xは、水素原子であるか、又は、同一又は異なって、ハロゲノ基、 C1[0069] X in the general formula (I) is a hydrogen atom, or the same or different, a halogeno group, C1
〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる 1〜3個 の基であるものが好ましい。 A group having 1 to 3 groups selected from the group consisting of a -C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group is preferred.
[0070] 一般式 (I)中の部分構造である、下記の式 (k) [0070] The following formula (k) which is a partial structure in the general formula (I)
[0071] [化 5]
Figure imgf000026_0001
[0071] [Chemical 5]
Figure imgf000026_0001
(式中、 *は、一般式 (I)中のイミダゾ [1 , 2— b]ピリダジン環の 3位及び基 C ( =〇 )一 Yとの結合位置を示し、 Xは前記と同じ意味を示す。）で表される基の好ましい具 (In the formula, * indicates the bonding position of the imidazo [1, 2-b] pyridazine ring in the general formula (I) with the 3-position and the group C (= O) 1 Y, and X has the same meaning as described above. A preferred component of the group represented by
Figure imgf000027_0001
Figure imgf000027_0001
[0076] [化 9] [0076] [Chemical 9]
Figure imgf000028_0001
Figure imgf000028_0001
(k-43) (k-44) (k-45) (k-46) (k-47) (k-48)
Figure imgf000028_0002
(k-43) (k-44) (k-45) (k-46) (k-47) (k-48)
Figure imgf000028_0002
(k-49) (k-50) Ck-B 1 )  (k-49) (k-50) Ck-B 1)
[0077] (式中、 *は前記と同じものを示す。）を挙げること力 Sでき、 [0077] (In the formula, * represents the same thing as described above.)
(k 1)、 （k 2)、 （k 3)、 （k 7)、 （k 8)、 （k 10)、 （k 12)、 （k 13)、 （k (k 1), (k 2), (k 3), (k 7), (k 8), (k 10), (k 12), (k 13), (k
17)及び (k 18)がより好まし!/、。 17) and (k 18) are more preferred!
[0078] 一般式 (I)の化合物は、 R1が水素原子；環 Aが 1 , 4 フエ二レン基；である下記の 一般式 (I a) [0078] The compound of the general formula (I) has the following general formula (I a) wherein R 1 is a hydrogen atom; and ring A is a 1,4-phenylene group;
[0079] [化 10] [0079] [Chemical 10]
Figure imgf000028_0003
Figure imgf000028_0003
[0080] (式中、 R2、 X及び Yは前記と同じものを示す。）で表される化合物、その塩又はそれ らの溶媒和物が好ましい。 [0080] (wherein R 2 , X and Y are as defined above), a salt thereof or a solvate thereof is preferred.
[0081] 一般式 (I)中の Yは、上記の式 (a)、 (c)、 （e)、 （f)、 （h)、 (i)又は (v)で表される基 が好ましぐ式 (a)、 （e)又は (v)で表される基がより好ましい。 [0081] Y in the general formula (I) is a group represented by the above formula (a), (c), (e), (f), (h), (i) or (v). A group represented by the formula (a), (e) or (v) is more preferable.
[0082] 一般式 (I)中の Yが式 (a)で表される基の場合、下記の式 (y)及び (ζ) [0082] When Y in the general formula (I) is a group represented by the formula (a), the following formulas (y) and (ζ)
[0083] [化 11] [0083] [Chemical 11]
Figure imgf000029_0001
Figure imgf000029_0001
[0084] (式中、 R3y及び ΙΤΖは、同一又は異なって、水素原子又は C1〜C6アルキル基を示 し、 [In the formula, R 3y and Ζ are the same or different and each represents a hydrogen atom or a C1-C6 alkyl group,
R4y及び R5yは、同一又は異なって、水素原子、 C1〜C6ァノレキノレ基、ハロゲノ C；!〜 C6ァノレキノレ基、 C1〜C6アルコキシ C1〜C6アルキル基、 C3〜C7シクロアルキル 基又は C 3〜 C 7シクロアルキル C；!〜 C 6アルキル基を示し、 R 4y and R 5y are the same or different and are a hydrogen atom, C1-C6 anolenoquinole group, halogeno C;! -C6 alkenoquinole group, C1-C6 alkoxy C1-C6 alkyl group, C3-C7 cycloalkyl group or C3- C 7 cycloalkyl C;! To C 6 alkyl group,
R6y、 R6z、 R7y、 R7z、 R8y、 R8z、 R9y及び R9zは、同一又は異なって、水素原子、ハロゲ ノ基、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C1〜C6アルコキシ C；!〜 C6ァノレキノレ基、水酸基、 C1〜C6アルコキシ基、ハロゲノ C1〜C6アルコキシ基又は C1〜C6アルコキシ C1〜C6アルコキシ基を示し、 R 6y , R 6z , R 7y , R 7z , R 8y , R 8z , R 9y and R 9z are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 anorequinole group, a halogeno C1-C6 alkyl group, C1-C6 alkoxy C;! -C6 alkenoquinole group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy C1-C6 alkoxy group,
R15z、 R16z及び R17zは、同一又は異なって、水素原子、ハロゲノ基、 C1〜C6アルキ ル基、ハロゲノ C1〜C6アルキル基、 C1〜C6アルコキシ C1〜C6アルキル基、水酸 基、 C1〜C6アルコキシ基、ハロゲノ C1〜C6アルコキシ基又は C1〜C6アルコキシ C1〜C6アルコキシ基を示す。）で表される基がさらに好ましい。 R 15z , R 16z and R 17z are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a hydroxyl group, C1 -C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy C1-C6 alkoxy group is shown. ) Is more preferable.
[0085] 一般式 (I)の化合物は、 Yが上記の式 (y)及び (z)； R1が水素原子；環 Aが 1 , 4 フ ェニレン基；である下記の一般式 (I b)及び (I c) [0085] The compound of the general formula (I) has the following general formula (I b) wherein Y is the formula (y) and (z) above; R 1 is a hydrogen atom; and the ring A is a 1,4-phenylene group. ) And (I c)
[0086] [化 12] [0086] [Chemical 12]
Figure imgf000030_0001
Figure imgf000030_0001
[0087] (式中、 R2、 R3y、 R3z、 R4y、 R5y、 R6y、 R7y、 R8y、 R9y、 R6z、 R7z、 R8z、 R9z、 R15z、 R16z、 R17z及び Xは前記と同じものを示す。 ) [0087] (wherein R 2 , R 3y , R 3z , R 4y , R 5y , R 6y , R 7y , R 8y , R 9y , R 6z , R 7z , R 8z , R 9z , R 15z , R 16z , R 17z and X are the same as above.)
で表される化合物、その塩又はそれらの溶媒和物がより好まし!/、。  A compound represented by the formula: salt thereof or solvate thereof is more preferred!
[0088] 式 (y)及び（z)中の R3y及び R3zは、同一又は異なって、水素原子及びメチル基が 好ましい。 [0088] R 3y and R 3z in the formulas (y) and (z) are the same or different and are preferably a hydrogen atom and a methyl group.
[0089] 式 (y)及び (z)中の R6y、 R6z、 R7y、 R7z、 R8y、 R8z、 R9y及び R9zは、同一又は異なつ て、水素原子及び C1〜C6アルキル基が好ましい。 [0089] In the formulas (y) and (z), R 6y , R 6z , R 7y , R 7z , R 8y , R 8z , R 9y and R 9z are the same or different and represent a hydrogen atom and C1 to C6. Alkyl groups are preferred.
[0090] 上記の式 (y)及び（z)の好ましい具体例としては、下記の（y—；！)〜（y— 24)及び（ z—；!）〜（z— 24) [0090] Preferable specific examples of the above formulas (y) and (z) include the following (y- ;!) to (y-24) and (z- ;!) to (z-24).
[0091] [化 13] [0091] [Chemical 13]
Figure imgf000030_0002
Figure imgf000030_0002
(y-s) (y- 1 0) (y- 1 1 ) (y- 1 2)  (y-s) (y- 1 0) (y- 1 1) (y- 1 2)
[0092] [化 14]
Figure imgf000031_0001
[0092] [Chemical 14]
Figure imgf000031_0001
[9ΐ¾] [ 600]  [9ΐ¾] [600]
"、、ノ ' ■1、",, no '■ 1,
Figure imgf000031_0002
Figure imgf000031_0002
[9ΐ¾] 600]  [9ΐ¾] 600]
Figure imgf000031_0003
Figure imgf000031_0003
C66CZ.0/Z.00idf/X3d 63 2893Ζ.0/8002 OAV [0095] で表される基を挙げることができ、 (y— 2)、 （y— 3)、 （y— 4)、 （y— 5)、 （y— 8)、 (y 14)、 （y— 15)、 （y— 16)、 （y— 17)、 （y— 20)、 (z— 1)、 (z— 2)、 （z— 3)、 （z— 4)、 （z— 5)、 （z— 6)、 （z— 9)、 （z— 13)、 （z— 14) (z— 15)、 （z— 16)、 （z— 17)及 び（z 18)がより好ましい。 C66CZ.0 / Z.00idf / X3d 63 2893Ζ.0 / 8002 OAV [0095] and (y—2), (y—3), (y—4), (y—5), (y—8), (y14), (y y—15), (y—16), (y—17), (y—20), (z—1), (z—2), (z—3), (z—4), (z— 5), (z-6), (z-9), (z-13), (z-14) (z-15), (z-16), (z-17) and (z18) are More preferred.
[0096] Yは、式（z)で表される基が好まし!/、。  [0096] Y is preferably a group represented by the formula (z)! /.
[0097] 式 (z)中の R15z、 R16z及び R17zは、同一又は異なって、水素原子、ハロゲノ基、 C1 〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基及び C1〜C6アルコキシ基が好まし い。 [0097] R 15z , R 16z and R 17z in the formula (z) are the same or different and are preferably a hydrogen atom, a halogeno group, a C1-C6 anolenoquinole group, a halogeno C1-C6 alkyl group or a C1-C6 alkoxy group. Good.
一般式 (I)中の Yが式 (e)で表される基である場合、式 (e)中の R3eは、水素原子が 好ましぐ R4eは、水素原子が好ましぐ R12e、 R13e及び R14eは、同一又は異なって、水 素原子、ハロゲノ基又は C1〜C6アルコキシ基が好ましぐ oは、 0が好ましい。 一般式 (I)中の Yが式 (V)で表される基である場合、式 (V)中の R3vは、水素原子が 好ましぐ R12e、 R13e及び R14eは、同一又は異なって、水素原子又は C1〜C6アルキ ル基が好ましぐ qは、 1が好ましぐ Vは、 3—モルホリニル基又は 4 モルホリニル基 が好ましい。 When Y in general formula (I) is a group represented by formula (e), R 3e in formula (e) is preferably a hydrogen atom R 4e is preferably a hydrogen atom R 12e R 13e and R 14e are the same or different, and a hydrogen atom, a halogeno group, or a C1-C6 alkoxy group is preferred, and o is preferably 0. When Y in general formula (I) is a group represented by formula (V), R 3v in formula (V) is preferably a hydrogen atom, R 12e , R 13e and R 14e are the same or Differently, a hydrogen atom or a C1-C6 alkyl group is preferred. Q is preferably 1. V is preferably a 3-morpholinyl group or a 4-morpholinyl group.
[0098] 一般式（I)の化合物中、下記の式（II一；!）〜（II 44)  [0098] Among the compounds of the general formula (I), the following formulas (II I ;!) to (II 44)
[0099] [化 17] [0099] [Chemical 17]
Figure imgf000032_0001
Figure imgf000032_0001
( I I - 1 ) ( I 1 - 2 ) ( I 1 - 3 )
Figure imgf000032_0002
[0100] [化 18] (II-1) (I 1-2) (I 1-3)
Figure imgf000032_0002
[0100] [Chemical 18]
Figure imgf000033_0001
Figure imgf000033_0001
C I I l o) C I I 1 ) ( I 1 - 1 2)  C I I l o) C I I 1) (I 1-1 2)
[0101] [化 19]  [0101] [Chemical 19]
Figure imgf000033_0002
Figure imgf000033_0002
( I 1 - 1 6 ) ( I 1 - 1 7 ) ( 1 1 — 1 8〉 (I 1-1 6) (I 1-1 7) (1 1-1 8)
[0102] [化 20] [0102] [Chemical 20]
Figure imgf000034_0001
Figure imgf000034_0002
Figure imgf000034_0001
Figure imgf000034_0002
( I 1 - 2 2) ( I I 2 3 ) ( I I 24 ) (I 1-2 2) (I I 2 3) (I I 24)
[0103] [化 21]
Figure imgf000034_0003
[0103] [Chemical 21]
Figure imgf000034_0003
( I 1 - 2 5 ) ( I 1 - 2 6 ) ( I 1 - 2 7 )
Figure imgf000034_0004
(I 1-2 5) (I 1-2 6) (I 1-2 7)
Figure imgf000034_0004
( 1 1 — 2 8 ) ( I 1 - 2 9 ) ( I 1 - 3 0 ) (1 1-2 8) (I 1-2 9) (I 1-3 0)
[0104] [化 22] [0104] [Chemical 22]
Figure imgf000035_0001
Figure imgf000035_0001
( I 1 - 40) ( I 1 - 1 ) ( I I 4 2)
Figure imgf000035_0002
(I 1-40) (I 1-1) (II 4 2)
Figure imgf000035_0002
( I 1 - 4 3) ( I 1 - 4) [0106] で表される化合物又は実施例 45〜71に記載の化合物、その塩又はそれらの溶媒和 物が好ましい。 (I 1-4 3) (I 1-4) [0106] or a compound described in Examples 45 to 71, a salt thereof, or a solvate thereof is preferable.
一般式 (I)の化合物中、式 (II 1)、 (II 2)、（II 3)、（II 4)、（II 5)、（II 6 )、（11— 7)、（11— 8)、（11— 9)、 (II 10)、 (II 11)、 (11—12)、（11—13)、 (II- 1 4)、（II 15)、（II 16)、（II 17)、（II 18)、（II 19)、（II 20)、（II 21)、 ( II 22)、（II 23)、 (Π— 24)及び（II 25)で表される化合物、その塩又はそれら の溶媒和物がより好ましい。  Among the compounds of general formula (I), the compounds of formula (II 1), (II 2), (II 3), (II 4), (II 5), (II 6), (11-7), (11-8) ), (11-9), (II 10), (II 11), (11-12), (11-13), (II-14), (II 15), (II 16), (II 17 ), (II 18), (II 19), (II 20), (II 21), (II 22), (II 23), (Π-24) and (II 25), and salts thereof Or solvates thereof are more preferred.
また、一般式 (I)の化合物中のより好ましい化合物としては、実施例 46、 47、 48、 5 1、 52、 53、 54、 55、 56、 60、 61、 67、 69又は 71に記載のィ匕合物、その塩又はそ れらの溶媒和物も挙げられる。  Further, more preferable compounds among the compounds of the general formula (I) are those described in Examples 46, 47, 48, 51, 52, 53, 54, 55, 56, 60, 61, 67, 69 or 71. Or a salt thereof or a solvate thereof.
[0107] さらに、一般式 (I)の化合物は下記の [0107] Furthermore, the compound of the general formula (I) is
4- [6 - [ (3, 4ージクロ口ベンジル）ァミノ]イミダゾ [1 , 2— b]ピリダジンー3 ィル] N— [2—（ジメチルァミノ）ェチル]ベンズアミド、  4- [6-[(3,4-Dichloro-benzyl) amino] imidazo [1,2-b] pyridazine-3-yl] N— [2- (dimethylamino) ethyl] benzamide,
4- [6- [ ： /クロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジ:ンー 3- —ィルコ 4- [6-[: / Chlopropylmethyl) amino] imidazo [1,2-b] pyridazi: n 3-ilco
N- - (2—アミ ：ノエチル）ベンズアミド、 N--(2-Ami: Noethyl) benzamide,
4- [6- [ ： /クロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジ:ンー 3- —ィルコ 4- [6-[: / Chlopropylmethyl) amino] imidazo [1,2-b] pyridazi: n 3-ilco
N- - [2 -（ィソプロピルァミノ）ェチル]ベンズアミド、 N-[2- (Isopropylamino) ethyl] benzamide,
4- [6- [ ： /クロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジ:ンー 3- —ィルコ 4- [6-[: / Chlopropylmethyl) amino] imidazo [1,2-b] pyridazi: n 3-ilco
N- - [2— (ジメチルァミノ）ェチル]ベンズアミド、 N--[2— (Dimethylamino) ethyl] benzamide,
4- [6- [ ： /クロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジ:ンー 3- —ィルコ 4- [6-[: / Chlopropylmethyl) amino] imidazo [1,2-b] pyridazi: n 3-ilco
N- - [2— (ジメチルァミノ）ェチル] N メチルベンズアミド、 N--[2— (Dimethylamino) ethyl] N methylbenzamide,
( ± )— 4— [ 6 [ (シクロプロピルメチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3 ィ ル]—N—[ (1R, 2R) - 2- (ジメチルァミノ）シクロへキシル]ベンズアミド、  (±) — 4— [6 [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3 yl] —N— [(1R, 2R) -2- (dimethylamino) cyclohexyl] benzamide,
[ (3R)— 3— (ジメチノレアミノ）ピロリジン一 1—ィル] = [4— [6— [ (シクロプロピルメチ ル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン— 3 ィル]フエニル] =ケトン、  [(3R) — 3— (Dimethylolamino) pyrrolidine 1-yl] = [4— [6— [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine-3 yl] phenyl] = Ketones,
( ± )— 4— [ 6 [ (シクロプロピルメチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3 ィ ル] N— [ (1R, 2R) - 2- (ジメチルァミノ）シクロペンチル]ベンズアミド、  (±) — 4— [6 [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3 yl] N— [(1R, 2R)-2- (dimethylamino) cyclopentyl] benzamide,
[ (2R)— 2— [ [ (3R)— 3—フルォロピロリジン一 1—ィル]メチル]ピロリジン一 1—ィ ノレ] = [4— [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィ ノレ]フエニル] =ケトン、 [(2R) — 2— [[(3R) — 3-Fluoropyrrolidine 1-yl] methyl] pyrrolidine 1 1- Nore] = [4— [6 [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3 ynole] phenyl] = ketone,
4— [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン一 3 ィル] - N— [2—（ジメチルァミノ）ェチル ] 2—メチルベンズアミド、  4- [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -N- [2- (dimethylamino) ethyl] 2-methylbenzamide,
4 [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル] N— [2 （ジメチルァミノ）ェチル ] 3 メチルベンズアミド、  4 [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] N- [2 (dimethylamino) ethyl] 3 methylbenzamide,
5— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン一 3—ィル] - 5— [6— [(Cyclopropylmethyl) amino] imidazo [1, 2-b] pyridazine 1-yl]-
N— [2—（ジメチルァミノ）ェチル]チォフェン 2—カルボキサミド、 N— [2- (dimethylamino) ethyl] thiophene 2-carboxamide,
4— [ 6— [(シクロプロピノレメチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3—ィル] - 4— [6— [(Cyclopropinolemethyl) amino] imidazo [1, 2— b] pyridazine 3-yl]-
N— [2— [(3R)— 3—フルォロピロリジン 1—ィル]ェチル]ベンズアミド、 N— [2 — [(3R) —3-Fluoropyrrolidine 1-yl] ethyl] benzamide,
4 [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3—ィル ]ー2 フルオロー N— [3 （ジメチルァミノ）プロパンー2 ィル]ベンズアミド、  4 [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2 fluoro-N- [3 (dimethylamino) propane-2-yl] benzamide,
4— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン一 3—ィル]—2 フルオロー N メチノレー N— [2—（ジメチルァミノ）ェチル]ベンズアミド、  4— [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-1-yl] -2 fluoro-N-methylolene N— [2- (dimethylamino) ethyl] benzamide,
4-[6-[ (シクロプロピルメチノレ）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3 ィノレ]― 2 ーフルォロー^^ー[[(23)—1ーメチルピロリジンー2—ィル]メチル]べンズァミド、 4- [6-[(Cyclopropylmethinole) amino] imidazo [1,2-b] pyridazine 3-inole] -2-Fluoro ^^-[[(23) -1-Methylpyrrolidine-2-yl] methyl] Bensamide,
4— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン一 3—ィル]—24— [6 — [(Cyclopropylmethyl) amino] imidazo [1, 2-b] pyridazine 1-yl] -2
—フルォロ N メチル N— (1—メチルピロリジン 3—ィル）ベンズアミド、—Fluoro N Methyl N— (1-Methylpyrrolidine 3-yl) benzamide,
4— [6 [ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィノレ 2 フルオロー N—[[(2S, 4S)— 4 フルォロピロリジンー2 ィル]メチル]ベンズァ ミド、 4— [6 [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3 inole 2 fluoro-N — [[(2S, 4S) — 4 fluoropyrrolidine-2-yl] methyl] benzamide,
[ (2R)— 2 (ピロリジン一 1—ィルメチル)ピロリジン一 1—ィル] =[4-[6-[ (シク ロブチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン一 3 ィル]フエ二ノレ] =ケトン、 4 [6 （シクロブチルァミノ）イミダゾ [ 1 , 2— b]ピリダジン 3 ィル] 2 フルォ ロー N— [2—（ジメチルァミノ）ェチル]ベンズアミド、  [(2R) — 2 (Pyrrolidine 1-ylmethyl) pyrrolidine 1-yl] = [4- [6- [(Cyclobutyl) amino] imidazo [1, 2— b] Pyridazine 1 3-yl] Nore] = ketone, 4 [6 (cyclobutylamino) imidazo [1, 2— b] pyridazine 3 yl] 2 fluoro N— [2- (dimethylamino) ethyl] benzamide,
4 [6 （シクロブチルァミノ）イミダゾ [1， 2— b]ピリダジンー3 ィル ]ー2 フルォ ロー N— [2—（ジェチルァミノ）ェチル]ベンズアミド、  4 [6 (Cyclobutylamino) imidazo [1,2-b] pyridazine-3-yl] -2 fluoro N— [2- (Jetylamino) ethyl] benzamide,
4— [6 [ (シクロブチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3 ィル] 2 フル オロー N— [ 2—ピロリジン一 1—ィルェチル]ベンズアミド、 4— [6 [(Cyclobutyl) amino] imidazo [1, 2— b] pyridazine 3 yl] 2 Full Oro N— [2-Pyrrolidine 1-ylethyl] benzamide,
4— [6 [ (シクロプロピルメチル）ァミノ]イミダゾ [ 1， 2— b]ピリダジン 3 ィル] - 2 -フルォロ N— [(2S)—ピロリジン一 2—ィルメチル]ベンズアミド、  4— [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3-yl] -2-fluoro N — [(2S) -pyrrolidine-1-2-methylmethyl] benzamide,
4-[6-[(3-クロ口ベンジル）ァミノ]イミダゾ [ 1， 2— b]ピリダジン 3 ィル]― N 4- [6-[(3-Chlorobenzyl) amino] imidazo [1,2-b] pyridazine 3-yl]-N
[2—（ジメチルァミノ）ェチル]ベンズアミド、及び  [2- (dimethylamino) ethyl] benzamide, and
4— [6— [ (4 メトキシベンジル）ァミノ]イミダゾ [ 1， 2— b]ピリダジン 3 ィル]― N  4— [6— [(4 Methoxybenzyl) amino] imidazo [1,2-b] pyridazine 3 yl]-N
[2—（ジメチルァミノ）ェチル]ベンズアミド  [2 -— (Dimethylamino) ethyl] benzamide
からなる群より選ばれるレ、ずれか 1つの化合物、その塩又はそれらの溶媒和物が好ま しい。 Preferred is one selected from the group consisting of: one compound, a salt thereof, or a solvate thereof.
また、一般式 (I)の化合物は下記の  In addition, the compound of the general formula (I)
2—フルォロ 4— [ 6— [ (4 フルォロブチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン一 3 -ィル] N— [[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチル]ベンズアミ H\ 2—Fluoro 4— [6— [(4 Fluorobutyl) amino] imidazo [1, 2 — b] Pyridazine 1 3 -yl] N— [[(2S, 4R) — 4 Fluoropyrrolidine 1 2 yl] Methyl] benzami H \
4 [6— [(4—フルォロブチル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3—ィル]—N 4 [6— [(4-Fluorobutyl) amino] imidazo [1, 2— b] pyridazine 3-yl] —N
— [[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチル]ベンズアミド、 — [[(2S, 4R) — 4 fluoropyrrolidine-2-yl] methyl] benzamide,
2—フルォロ 4— [6— [( 3—フルォロプロピル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 2-Fluoro 4— [6— [(3-Fluoropropyl) amino] imidazo [1, 2 — b] pyridazine
— 3 ィル] N—[[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチル]ベンズァ ミト--、 — 3 yl] N — [[(2S, 4R) — 4 Fluoropyrrolidine-2-yl] methyl] benzamito--,
N-[[(2S, 4R)—4 フルォロピロリジン一 2 ィル]メチル]—4— (6— [[3 （メチ ルチオ）プロピル]ァミノ]イミダゾ [1 , 2-b]ピリダジン 3 ィル）ベンズアミド、  N-[[(2S, 4R) —4 Fluoropyrrolidine-2-yl] methyl] —4— (6— [[3 (methylthio) propyl] amino] imidazo [1, 2-b] pyridazine 3 Le) benzamide,
2 フルオロー N— [[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチル] 4— ( 6— [ [2 （メチルチオ）ェチル]ァミノ]イミダゾ [ 1， 2— b]ピリダジン 3 ィル）ベン ズアミド、 2 Fluoro-N — [[(2S, 4R) — 4 Fluoropyrrolidine-2-yl] methyl] 4— (6— [[2 (Methylthio) ethyl] amino] imidazo [1,2-b] pyridazine 3 Le) Benzamide,
4 [6— [(5 フルォロペンチル）ァミノ]イミダゾ [1， 2— b]ピリダジン 3 ィル] 4 [6 — [(5 Fluoropentyl) amino] imidazo [1,2-b] pyridazine 3 yl]
N [ [ (2S , 4R)— 4 フルォロピロリジン 2 ^ fル]メチル]ベンズアミド、 N [[(2S, 4R) —4 fluoropyrrolidine 2 ^ f] methyl] benzamide,
2—フルォロ 4 [6 [( 5—フルォロペンチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 2—Fluoro 4 [6 [(5 —Fluoropentyl) amino] imidazo [1, 2 — b] pyridazine
— 3 ィル] N— [[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチル]ベンズァ ミド、 2—フルォロ 4— [6— [ (6—フルォ口へキシル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン — 3 ィル] N— [ [ (2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチノレ]ベンズァ ミド、 — 3 yl] N— [[(2S, 4R) — 4 fluoropyrrolidine- 1 yl] methyl] benzamide, 2—Fluoro 4— [6— [(6-Fluorohexyl) amino] imidazo [1, 2 — b] Pyridazine — 3 yl] N— [[(2S, 4R) — 4 Fluoropyrrolidine 1 2 Il] Mechinore] Benzamide,
4 [6— [ (6 フルォ口へキシル）ァミノ]イミダゾ [1 , 2—b]ピリダジンー3 ィル] N- [ [ (2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチル]ベンズアミド、  4 [6— [(6 Fluorohexyl) amino] imidazo [1, 2—b] pyridazine-3 yl] N- [[(2S, 4R) — 4 Fluoropyrrolidine-2-yl] methyl] benzamide ,
2 フルオロー N— [ [ (2R, 3S)— 3 メトキシピロリジン一 2 ィル]メチル ]—4— (6 一 [ [2—（メチルチオ）ェチル]ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3—ィル）ベンズ アミド、 2 Fluoro-N— [[(2R, 3S) — 3 Methoxypyrrolidine-2-yl] methyl] —4— (6 1 [[2- (Methylthio) ethyl] amino] imidazo [1, 2— b] pyridazine 3— Yil) Benz Amido,
2—フルォロ 4— [6— [ (4 フルォロブチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3 ィル]—N—[ [ (2R, 3S)— 3 メトキシピロリジンー2 ィル]メチル]ベンズアミド  2—Fluoro 4— [6— [(4 Fluorobutyl) amino] imidazo [1, 2 — b] pyridazine 3 yl] —N— [[(2R, 3S) — 3 methoxypyrrolidine-2 yl] methyl] benzamide
2 フルオロー 4 [6— [ (3 フルォロプロピル）ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィル]—N—[ [ (2R, 3S)— 3 メトキシピロリジンー2 ィル]メチル]ベンズァ ミド、 2 fluoro-4 [6— [(3 fluoropropyl) amino] imidazo [1, 2— b] pyridazine 3 yl] —N— [[(2R, 3S) — 3 methoxypyrrolidine-2 yl] methyl] benzamide,
2—フルォロ 4— [6— [ (4—フルォロブチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 2—Fluoro 4— [6— [(4-Fluorobutyl) amino] imidazo [1, 2 — b] pyridazine
3 ィル] N— [ [ ( 2 S )— 1 メチルピロリジン 2 ィル]メチル]ベンズアミド、及び 2—フルォロ 4— [6— [ (4 フルォロ 3 メチルブチル）ァミノ]イミダゾ [ 1 , 2—b ]ピリダジン一 3 ィル] N— [ [ ( 2 S , 4R)— 4 フルォロピ口リジン一 2 ィル]メチ ノレ]ベンズアミド 3yl] N — [[(2S) —1methylpyrrolidine 2yl] methyl] benzamide and 2-fluoro 4— [6 — [(4 fluoro 3methylbutyl) amino] imidazo [1, 2—b] 1 pyridazine 3 N] N— [[(2 S, 4R) — 4 fluoropirine lysine 1 2 yl] methylol] benzamide
力、らなる群より選ばれるいずれ力、 1つの化合物、その塩又はそれらの溶媒和物も好ま しい。 A force, any force selected from the group, one compound, a salt thereof or a solvate thereof is also preferred.
本発明の一般式 (I)で表される化合物が、アミノ基等の塩基性基を有する場合、所 望により医薬的に許容される塩とすることができる。そのような塩としては、例えばフッ 化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩等のハロゲン化水素酸塩;硝 酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩;メタンスルホン酸塩、トリフルォロ メタンスルホン酸塩、エタンスルホン酸塩等の低級アルカンスルホン酸塩；ベンゼンス ルホン酸塩、 p トルエンスルホン酸塩等のァリールスルホン酸塩；酢酸、りんご酸、 フマル酸塩、コハク酸塩、クェン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸 塩;及びオル二チン酸塩、グルタミン酸塩、ァスパラギン酸塩等のアミノ酸塩；を挙げ ること力 sでき、ハロゲン化水素酸塩及び有機酸塩が好ましい。また、一般式 (I)で表さ れる本発明化合物が、カルボキシ基等の酸性基を有する場合、一般的に塩基付加 塩を形成することが可能である。医薬的に許容される塩としては、例えばナトリウム塩 、カリウム塩、リチウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアル カリ土類金属塩；アンモニゥム塩等の無機塩；ジベンジルァミン塩、モルホリン塩、フ ェニルグリシンアルキルエステル塩、エチレンジァミン塩、 N—メチルダルカミン塩、ジ ェチルァミン塩、トリエチルァミン塩、シクロへキシルァミン塩、ジシクロへキシルァミン 塩、 N, N'—ジベンジルエチレンジァミン塩、ジエタノールアミン塩、 N—ベンジル— N- (2—フエニルエトキシ）アミン塩、ピぺラジン塩、テトラメチルアンモニゥム塩、トリ ス（ヒドロキシメチル)ァミノメタン塩等の有機アミン塩；等を挙げること力 Sできる。 When the compound represented by the general formula (I) of the present invention has a basic group such as an amino group, it can be converted into a pharmaceutically acceptable salt as desired. Such salts include, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfate, phosphate Inorganic acid salts such as methane sulfonate, trifluoro methane sulfonate, lower alkane sulfonate such as ethane sulfonate, benzene sulfonate, p Aryl sulfonate such as toluene sulfonate, acetic acid, apple Organic acids such as acid, fumarate, succinate, succinate, tartrate, succinate, maleate And amino acid salts such as ornithate, glutamate, and aspartate; hydrohalides and organic acid salts are preferred. In addition, when the compound of the present invention represented by the general formula (I) has an acidic group such as a carboxy group, it is generally possible to form a base addition salt. Examples of pharmaceutically acceptable salts include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; dibenzylamine salt and morpholine. Salt, phenylglycine alkyl ester salt, ethylene diamine salt, N-methyl darcamamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt , Diethanolamine salts, N-benzyl-N- (2-phenylethoxy) amine salts, piperazine salts, tetramethylammonium salts, organic amine salts such as tris (hydroxymethyl) aminomethane salts; Power S can be.
[0109] 本発明の一般式 (I)で表される化合物又はその塩は、遊離体もしくは溶媒和物とし て存在することもある。溶媒和物としては、医薬的に許容し得るものであれば特に限 定されないが、具体的には、水和物、エタノール和物等が好ましい。また、一般式 (I) で表される本発明化合物中に窒素原子が存在する場合には N—ォキシド体となって V、てもよく、これら溶媒和物及び N—ォキシド体も本発明の範囲に含まれる。  [0109] The compound represented by the general formula (I) of the present invention or a salt thereof may exist as a free form or a solvate. The solvate is not particularly limited as long as it is pharmaceutically acceptable, and specifically, a hydrate, an ethanolate, and the like are preferable. In addition, when a nitrogen atom is present in the compound of the present invention represented by the general formula (I), it may be an N-oxide and may be V, and these solvates and N-oxides are also present in the present invention. Included in the range.
[0110] 一般式 (I)で表される本発明化合物、その塩又はそれらの溶媒和物は、置換基の 種類や組み合わせによって、シス体、トランス体等の幾何異性体、互変異性体又は d 体、 1体等の光学異性体等の各種異性体が存在し得るが、本発明の化合物は、特に 限定して!/、な!/、場合はそれら全ての異性体、立体異性体及びレ、ずれの比率のこれ ら異性体及び立体異性体混合物をも包含するものである。  [0110] The compound of the present invention represented by the general formula (I), a salt thereof, or a solvate thereof may be a geometric isomer such as a cis isomer or a trans isomer, a tautomer, There may be various isomers such as optical isomers such as d-form, 1-form, etc., but the compounds of the present invention are particularly limited! /, NA! /, in some cases, all isomers, stereoisomers and Also included are isomers and stereoisomer mixtures in the ratio of deviation and deviation.
[0111] また、本発明は、生体内における生理条件下で酵素や胃酸等による反応により本 発明の医薬組成物の有効成分である化合物 (I)に変換される化合物、すなわち、酵 素的に酸化、還元、加水分解等を起こして化合物（I)に変化される化合物又は胃酸 等により加水分解等を起こして化合物（I)に変化される「医薬的に許容されるプロドラ ッグ化合物」も本発明に包含する。  [0111] The present invention also relates to a compound that is converted into compound (I) that is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, enzymatically. There is also a “pharmaceutically acceptable prodrug compound” that is converted to compound (I) by oxidation, reduction, hydrolysis, etc., or is converted to compound (I) by hydrolysis or the like by gastric acid or the like. It is included in the present invention.
[0112] 上記プロドラッグとしては、化合物（I)にァミノ基が存在する場合には、そのアミノ基 がァシル化、アルキル化、りん酸化された化合物（例えば、そのアミノ基がエイコサノ ィル化、ァラエル化、ペンチルァミノカルボニル化、（5 メチノレ一 2 ォキソ 1 , 3 - ジォキソレン一 4—ィル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチ ノレ化、ビバロイルォキシメチル化、 tert ブチル化された化合物等である）等を挙げ ること力 Sでき、化合物（I)に水酸基が存在する場合には、その水酸基がァシル化、ァ ルキル化、りん酸化、ほう酸化された化合物（例えば、その水酸基がァセチル化、ノ ルミトイノレ化、プロパノィル化、ビバロイル化、サクシ二ル化、フマリル化、ァラエル化、 ジメチルァミノメチルカルボニル化された化合物等である。 )等を挙げること力 Sできる。 また、化合物（I)にカルボキシ基が存在する場合には、そのカルボキシ基がエステル 化、アミド化された化合物（例えば、そのカルボキシ基がェチル エステル化、フエ二 ノレ エステル化、カルボキシメチル エステル化、ジメチルァミノメチル エステル化、 ピバロィルォキシメチル エステル化、エトキシカルボニルォキシェチル エステル化 、アミド化又はメチルアミド化された化合物等である。）等が挙げられる。 [0112] As the prodrug, when an amino group is present in the compound (I), a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group is eicosano Silylation, araelation, pentylaminocarbonylation, (5 methinoyl-2-oxo1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethinolation, bivalyloxymethylation, tert In the case where the compound (I) has a hydroxyl group, the compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (such as a butylated compound). For example, a compound in which the hydroxyl group is acetylated, normitinoylated, propanoylated, bivalylated, succinylated, fumarylated, araerylated, dimethylaminomethylcarbonylated, etc. can be mentioned. . In addition, when a carboxy group is present in the compound (I), a compound in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenol esterified, carboxymethyl esterified, Dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxetyl esterification, amidation, or methylamidation compound).
[0113] 本発明の化合物のプロドラッグは公知の方法によって化合物（I)から製造すること 力 Sできる。また、本発明の化合物のプロドラッグは、広川書店 1990年刊「医薬品の開 発」第 7巻分子設計 163頁〜 198頁に記載されているような、生理的条件で化合物（I )に変化するものも含まれる。  [0113] A prodrug of the compound of the present invention can be produced from compound (I) by a known method. In addition, the prodrug of the compound of the present invention changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. Also included.
[0114] 一般式 (I)で表される化合物の製造方法について述べる。ただし、製造方法は、下 記の方法に何ら限定されるものではない。  [0114] A method for producing the compound represented by the general formula (I) will be described. However, the production method is not limited to the following method.
[0115] 一般式 (I)で表される化合物及びその製造中間体は、以下に述べる種々の公知の 反応を利用して製造することができる。その際、原料又は中間体の段階で官能基を 適当な保護基で保護する場合がある。このような官能基としては、例えば水酸基、力 ノレボキシ基、アミノ基等を挙げることができ、保護基の種類、並びにそれらの保護基 の導入と除去の条件は、例えば Protective Groups in Organic Synthesis (T . W. Green and P. G. M. Wuts, John Wiley & Sons, Inc. , New York , 1991)に記載のものを参考にすることができる。  [0115] The compound represented by the general formula (I) and production intermediates thereof can be produced by utilizing various known reactions described below. In this case, the functional group may be protected with an appropriate protecting group at the raw material or intermediate stage. Examples of such functional groups include a hydroxyl group, a force carboxy group, an amino group, and the like. The types of protecting groups and the conditions for introducing and removing these protecting groups are, for example, Protective Groups in Organic Synthesis (T W. Green and PGM Wuts, John Wiley & Sons, Inc., New York, 1991).
[0116] 本発明の化合物（I)は、下記の [製造法 1]により製造することができる。  [0116] Compound (I) of the present invention can be produced by the following [Production Method 1].
[製造法 1]  [Production method 1]
[0117] [化 24] [0117] [Chemical 24]
Figure imgf000042_0001
Figure imgf000042_0001
[0118] (式中、環 A、
Figure imgf000042_0002
R2、 X及び Yは前記と同じものを示す。） [0118] (wherein ring A,
Figure imgf000042_0002
R 2 , X and Y are the same as described above. )
[0119] 本発明の化合物（I)は、化合物（1)とァミン（2)との求核置換反応で化合物（3)を 製造し、化合物（3)からカルボン酸誘導体である化合物（4)を製造し、化合物（4)と アミン体（5)とを縮合して製造すること力 Sできる。  [0119] Compound (I) of the present invention is produced by producing compound (3) by nucleophilic substitution reaction between compound (1) and amine (2), and compound (4) which is a carboxylic acid derivative from compound (3). Can be produced by condensing the compound (4) with the amine (5).
[0120] 次に [製造法 1 ]の各行程を詳細に説明する。  [0120] Next, each step of [Production Method 1] will be described in detail.
[0121] [製造法 1 1]において、化合物（1)とァミン（2)の求核置換反応で化合物（3)を 製造する方法を説明する。  [0121] In [Production Method 1 1], a method for producing compound (3) by nucleophilic substitution reaction of compound (1) and amine (2) will be described.
[製造法 1 1]  [Production method 1 1]
[0122] [化 25] [0122] [Chemical 25]
Figure imgf000042_0003
Figure imgf000042_0003
[0123] (式中、 R1及び R2は前記と同じものを示す。） [Wherein R 1 and R 2 are the same as described above.]
[0124] 化合物（3)は、化合物（1)を塩基の存在下、化学量論のアミン（2)と処理する、求 核置換反応によって製造することができる。本反応は、塩基として、ァミン（2)を過剰 量用いてもよぐ反応溶媒を用いてもよい。ァミン（2)は、市販又は公知方法で製造し たものを用いればよい。或いは、化合物（3)は、化合物（1)と市販のアミンを反応させ た後に、公知の方法を用いて所望の R1及び/又は R2に導いて得ることもできる。例 えば、 R2にフルォロアルキル基を有する（3)を合成する際には、ヒドロキシアルキルァ ミンと（1)を反応させた後に、得られた化合物の、新たに導入された窒素原子を適当 な保護基で保護し、さらに無保護の水酸基にメタンスルホニル基などの脱離基を導 入して、テトラプチルアンモニゥムフルオリドなどを作用させることで得ることができる。 使用する塩基としては、例えばトリェチルァミン、ジイソプロピルェチルァミン等の有 機ァミン系塩基を挙げることができる。塩基の使用量は、化合物（1)に対して 2〜； 10 倍モル当量の範囲が好まし!/、。 [0124] Compound (3) is obtained by treating compound (1) with a stoichiometric amine (2) in the presence of a base. It can be produced by a nuclear substitution reaction. In this reaction, an excess amount of ammine (2) may be used as a base. The amine (2) may be commercially available or produced by a known method. Alternatively, the compound (3) can be obtained by reacting the compound (1) with a commercially available amine and then leading to the desired R 1 and / or R 2 using a known method. For example, when synthesizing (3) having a fluoroalkyl group at R 2 , after reacting hydroxyalkylamine with (1), the newly introduced nitrogen atom of the obtained compound is appropriately substituted. It can be obtained by protecting with a protecting group and introducing a leaving group such as a methanesulfonyl group into an unprotected hydroxyl group and allowing tetraptyl ammonium fluoride to act on it. Examples of the base used include organic amine bases such as triethylamine and diisopropylethylamine. The amount of base used is preferably 2 to 10 times the molar equivalent of compound (1)! /.
ァミン（2)の使用量としては、塩基を使用する場合は;!〜 2モル当量でよぐ塩基を 使用しなレ、場合は化合物（1)に対して 2〜30倍モル当量の範囲が好まし!/、。  The amount of amine (2) to be used is: when using a base;! ~ 2 molar equivalents should not be used with a base; in this case, the range of 2-30 molar equivalents relative to compound (1) I like it!
使用する溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれ ば特に制限はなぐ例えば N, N ジメチルホルムアミド（DMF)、 N メチルー 2—ピ 口リドン等のアミド系溶媒、ジメチルスルホキシド（DMSO)等のスルホキシド系溶媒等 を挙げること力 Sでき、 DMF、 DMSO等が好ましい。  The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, N, N dimethylformamide (DMF), amide solvents such as N methyl-2-pyridone, dimethyl Examples include sulfoxide solvents such as sulfoxide (DMSO), and DMF, DMSO and the like are preferable.
反応温度としては、 80〜； 160°Cの範囲が好ましい。  The reaction temperature is preferably in the range of 80 to 160 ° C.
反応時間は、通常 1〜24時間程度である。  The reaction time is usually about 1 to 24 hours.
[0125] [製造法 1— 2]において、化合物 (4)を製造する方法を説明する。 [0125] In [Production Method 1-2], a method for producing compound (4) will be described.
[製造法 1 2]  [Production method 1 2]
[0126] [化 26] [0126] [Chemical 26]
Figure imgf000043_0001
[0127] (式中、 R ^及び R bは、同一又は異なって、水素原子又は C1〜C6アルキル基を示 す力、、或いは R2°a及び R2°bがー体化して C1〜C6アルキレン基を形成してもよいこと を示し、 R21は、カルボキシ基、ホルミル基又は C1〜C6アルコキシカルボ二ル基を示 し、環 A、
Figure imgf000044_0001
R2及び Xは前記と同じものを示す。 )
Figure imgf000043_0001
(Wherein R ^ and R b are the same or different and represent a hydrogen atom or a C1 to C6 alkyl group, or R 2 ° a and R 2 ° b form a C1 ~ R 21 represents a carboxy group, a formyl group, or a C1-C6 alkoxycarbonyl group, and a ring A,
Figure imgf000044_0001
R 2 and X are the same as described above. )
[0128] カルボン酸誘導体である化合物（4)は、化合物（3)と有機ボロン酸誘導体（6)との カップリング反応で化合物（4a)を製造し、化合物（4a)を、（1) R21がホルミル基の場 合は酸化して、また（2) R21が C1〜C6アルコキシカルボニル基である場合は加水分 角早して、製造すること力 Sでさる。 [0128] Compound (4), which is a carboxylic acid derivative, is produced by coupling compound (3) and organic boronic acid derivative (6) to produce compound (4a). Compound (4a) is converted to (1) R When 21 is a formyl group, it is oxidized, and when (2) R 21 is a C1-C6 alkoxycarbonyl group, the angle of hydrolysis is increased and the production force S is reduced.
[0129] 化合物（4a)は、化合物（3)を、金属触媒及び塩基の存在下、有機ボロン酸誘導体  [0129] Compound (4a) is obtained by converting compound (3) into an organic boronic acid derivative in the presence of a metal catalyst and a base.
(6)とのカップリング反応により製造することができる。本カップリング反応では、反応 を促進するために適切な添加剤を使用してもよい。有機ボロン酸誘導体（6)は市販 又は公知の方法で製造可能であり、有機ボロン酸誘導体（6)の製造法及びカツプリ ング反応の参考文献としては、「Chemical Reviews, 1995, 95, 2457— 2483」 を挙げること力 Sでさる。  It can be produced by a coupling reaction with (6). In this coupling reaction, an appropriate additive may be used to accelerate the reaction. The organic boronic acid derivative (6) is commercially available or can be produced by a known method. References for the production method and the coupling reaction of the organic boronic acid derivative (6) include “Chemical Reviews, 1995, 95, 2457-2483”. I ’ll give you the power S.
有機ボロン酸誘導体（6)の使用量としては、化合物（3)の 1〜2倍モル当量の範囲 が望ましい。  The amount of the organic boronic acid derivative (6) used is preferably in the range of 1 to 2 molar equivalents of the compound (3).
金属触媒としてはパラジウム触媒が好ましぐ例えば [1 , —ビス（ジフエニルホス フイノ）フエ口セン]ジクロロパラジウム（II) /ジクロロメタン錯体（1： 1)、又はジクロロビ ス（トリフエニルホスフィン）パラジウム（II)及びテトラキス（トリフエニルホスフィン）パラ ジゥム（0)等を挙げることができる。金属触媒の使用量としては、化合物（3)に対して 0. 01—0. 2倍モル当量の範囲が好ましい。  Palladium catalysts are preferred as metal catalysts. For example, [1, bis (diphenylphosphino) phenocene] dichloropalladium (II) / dichloromethane complex (1: 1) or dichlorobis (triphenylphosphine) palladium (II). And tetrakis (triphenylphosphine) paradium (0). The amount of the metal catalyst used is preferably in the range of 0.01-0.2 molar equivalents relative to compound (3).
塩基としては、例えばリン酸三カリウム（水和物）、炭酸カリウム、炭酸セシウム等の 無機塩基類を挙げることができ、リン酸三カリウム（水和物）及び炭酸カリウム等が好 ましい。塩基の使用量としては、化合物（3)に対して 0. 2〜； 10倍モル当量の範囲が 好ましい。  Examples of the base include inorganic bases such as tripotassium phosphate (hydrate), potassium carbonate, cesium carbonate, etc. Tripotassium phosphate (hydrate) and potassium carbonate are preferred. The amount of the base used is preferably in the range of 0.2 to 10-fold molar equivalent to the compound (3).
添加剤としては、 1 , 1， 一ビス（ジフエニルホスフイノ）フエ口セン（dppf)、トリフエニル ホスフィン等の有機りん化合物が挙げられ、添加剤の使用量としては、化合物（3)に 対して 0. 05—0. 2モル当量の範囲が好ましい。 Examples of the additive include organic phosphorus compounds such as 1,1,1 bis (diphenylphosphino) phenocene (dppf), triphenylphosphine, and the amount of the additive used is compound (3). The range of 0.05-0.2 molar equivalent is preferred.
カップリング反応の溶媒としては、反応を阻害せず、出発物質をある程度溶解する ものであれば特に制限はなぐ例えば 1 , 4 ジォキサン、 1 , 2—ジメトキシェタン等 のエーテル系溶媒、 N, N ジメチルホルムアミド（DMF)、 N メチルー 2—ピロリド ン等のアミド系溶媒、トルエン、ベンゼン等の炭化水素系溶媒、メタノール、エタノー ル等のアルコール系溶媒、ァセトニトリル、水等の極性溶媒等が好ましぐこれらの溶 媒は、二種以上の混合溶媒として使用してもよい。  The solvent for the coupling reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, ether solvents such as 1,4 dioxane and 1,2-dimethoxyethane, N, N Amide solvents such as dimethylformamide (DMF) and N-methyl-2-pyrrolidone, hydrocarbon solvents such as toluene and benzene, alcohol solvents such as methanol and ethanol, polar solvents such as acetonitrile and water are preferred. These solvents may be used as a mixed solvent of two or more.
反応温度としては、 50°C〜溶媒の沸点の範囲であり、 70〜150°Cの範囲が好まし い。  The reaction temperature is in the range of 50 ° C to the boiling point of the solvent, preferably in the range of 70 to 150 ° C.
反応時間は、通常 1〜 50時間程度である。  The reaction time is usually about 1 to 50 hours.
[0130] (1) R21が、ホルミル基の場合 [0130] (1) When R 21 is a formyl group
化合物（4)は、アルデヒド誘導体である化合物（4a)を酸化して製造することができる Compound (4) can be produced by oxidizing compound (4a), which is an aldehyde derivative.
。酸化反応としては、例えば亜塩素酸ナトリウム等を用いた酸化が好ましぐ反応条 件の参考文献としては、実験化学講座 (第四版、 Vol. 22. 日本化学会編、丸善株 式会社）「有機合成 IV：酸 'アミノ酸'ペプチド、 P1〜P6」等を挙げること力 Sできる。 . As a reference for the reaction conditions where oxidation using sodium chlorite, etc., is preferred as an oxidation reaction, see Experimental Chemistry Course (4th edition, Vol. 22. The Chemical Society of Japan, Maruzen Co., Ltd.). “Organic synthesis IV: acid 'amino acid' peptide, P1 to P6” etc.
[0131] (2) R21が、 C1〜C6アルコキシカルボニル基の場合 [0131] (2) When R 21 is a C1-C6 alkoxycarbonyl group
化合物（4)は、 C1〜C6アルキルエステル誘導体である化合物（4a)を加水分解反 応して製造すること力 Sでさる。  The compound (4) can be obtained by the ability S to produce the compound (4a) which is a C1-C6 alkyl ester derivative by hydrolysis reaction.
加水分解反応は、公知のアルカリ加水分解が好ましぐ参考文献としては、実験化 学講座 (第四版、 Vol. 22. 日本化学会編、丸善株式会社）「有機合成 IV：酸 'ァミノ 酸'ペプチド、 P6〜P11」等を挙げること力 Sできる。  The reference for the hydrolysis reaction is that the known alkaline hydrolysis is preferred. Experimental Chemistry Course (4th edition, Vol. 22. The Chemical Society of Japan, Maruzen Co., Ltd.) “Organic Synthesis IV: Acid 'Amino acid” 'Peptides, P6-P11' etc.
[0132] [製造法 1— 3]において、化合物（4)とァミン体（5)との縮合反応により化合物（I)を 製造する方法を説明する。 [0132] In [Production Method 1-3], a method for producing Compound (I) by a condensation reaction between Compound (4) and amine compound (5) will be described.
[製造法 1 3]  [Production method 1 3]
[0133] [化 27] [0133] [Chemical 27]
Figure imgf000046_0001
Figure imgf000046_0001
[0134] (式中、環 A、
Figure imgf000046_0002
R2、 X及び Y前記と同じものを示す。 ) [0134] (wherein ring A,
Figure imgf000046_0002
R 2 , X and Y are the same as above. )
[0135] 化合物 (I)は、化合物 (4)を縮合剤の存在下、アミン体（5)と縮合して製造すること ができる。本縮合反応は、反応を促進するために、塩基及び/又は添加剤の存在下 に行ってもよい。アミン体（5)は、市販であるか、又は後述の方法で製造できる。 アミン体（5)の使用量としては、化合物（4)に対して 0. 6〜4. 0倍モル当量の範囲 が好ましい。  [0135] Compound (I) can be produced by condensing compound (4) with amine compound (5) in the presence of a condensing agent. This condensation reaction may be performed in the presence of a base and / or an additive in order to accelerate the reaction. The amine body (5) is commercially available or can be produced by the method described below. The amount of the amine compound (5) used is preferably in the range of 0.6 to 4.0 times molar equivalent to the compound (4).
縮合剤としては、例えば 1ーェチルー 3—（3—ジメチルァミノプロピル)カルポジイミ ド 塩酸塩（EDC)、ベンゾトリァゾールー 1 ィルォキシトリス（ジメチルァミノ）ホスホ ニゥム へキサフルォロホスフェート（BOP)、 O ベンゾトリアゾール 1—ィル一 N, N, Ν' , Ν， 一テトラメチルゥロニゥム へキサフルォロホスフェート、 4— (4, 6—ジメト キシ— 1 , 3, 5—トリァジン— 2—ィル）—4—メチルモルホリニゥム クロリド及びその 同類物等を挙げること力 Sでき、 1—ェチル 3— (3—ジメチルァミノプロピル)カルボ ジイミド 塩酸塩（EDC)、ベンゾトリァゾールー 1 ィルォキシトリス（ジメチルァミノ） ホスホニゥム へキサフルォロホスフェート（ΒΟΡ)、 Ο ベンゾトリアゾール 1—ィル — Ν, Ν, Ν' , Ν， 一テトラメチルゥロニゥム へキサフルォロホスフェート及び 4— (4, 6 ジメトキシ一 1 , 3, 5 トリァジン一 2 ィル） 4 メチルモルホリニゥム クロリド が好ましい。縮合剤の使用量としては、化合物（4)に対して 0. 8〜3倍モル当量の範 囲が好ましい。  Examples of the condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), benzotriazole-1yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O benzotriazole 1—yl N, N, Ν ', Ν, 1 tetramethyluronium hexafluorophosphate, 4— (4, 6-dimethoxy-1, 3,4,5-triazine-2-yl ) -4-Methylmorpholinum chloride and the like, etc. 1-Ethyl 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), benzotriazole-1-iloxytris ( Dimethylamino) phosphonium hexafluorophosphate (ΒΟΡ), Ο benzotriazole 1-yl — Ν, Ν, Ν ', Ν, monotetramethyluronium hexafluoro Sufeto and 4- (4, 6-dimethoxy one 1, 3, 5 Toriajin one 2 I le) 4-methyl morpholinium Niu beam chloride is preferred. The amount of the condensing agent used is preferably in the range of 0.8 to 3 molar equivalents relative to compound (4).
反応溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば 特に制限はなぐ例えば Ν, Ν ジメチルホルムアミド、 Ν メチルー 2—ピロリドン等 のアミド系溶媒、ジクロロメタン、クロ口ホルム等のハロゲン化炭化水素系溶媒、ジェ チルエーテル、テトラヒドロフラン等のエーテル系溶媒、トルエン、ベンゼン等の炭化 水素系溶媒等が好ましぐこれらの溶媒は、二種以上の混合溶媒として使用してもよ い。 The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, amide solvents such as Ν, ジ メ チ ル dimethylformamide, Ν methyl-2-pyrrolidone, dichloromethane, black mouth form, etc. Halogenated hydrocarbon solvent These solvents, which are preferably ether solvents such as tilether and tetrahydrofuran, and hydrocarbon solvents such as toluene and benzene, may be used as a mixed solvent of two or more.
添加剤としては、例えば 1—ヒドロキシベンゾトリアゾール（HOBt)等を挙げることが できる。添加剤を使用する場合の使用量は、化合物（4)に対して 0. ；!〜 1倍モル当 量の範囲が好ましい。  Examples of the additive include 1-hydroxybenzotriazole (HOBt). When the additive is used, the amount used is preferably in the range of 0.;! To 1-fold molar equivalent to the compound (4).
塩基としては、例えばトリェチルァミン、ジイソプロピルェチルァミン等の有機アミン 系塩基類等を好ましいものとして挙げることができる。塩基を使用する場合の使用量 は、化合物（4)に対して 1〜8倍モル当量の範囲が好まし!/、。  Preferred examples of the base include organic amine bases such as triethylamine and diisopropylethylamine. When using a base, the amount used is preferably in the range of 1 to 8 molar equivalents relative to compound (4)! /.
反応温度としては、 0°C〜溶媒の沸点の範囲が好まし!/、。  The reaction temperature is preferably in the range of 0 ° C to the boiling point of the solvent! /.
反応時間は、通常 1時間〜 4日間程度である。  The reaction time is usually about 1 hour to 4 days.
本製造法で得られた、化合物 (I)の基 Y上にアミノ基等の官能基を有する場合、当 該ァミノ基等の官能基は保護されていてもよぐ当該保護基の除去は前述のように一 般的に汎用される方法を用いればよい。更に、そのアミノ基は一般的な方法によりァ ルキル化等を行って、置換アミノ基に変換することができる。  When a functional group such as an amino group is present on the group Y of the compound (I) obtained by this production method, the functional group such as the amino group may be protected. A generally used method such as the above may be used. Further, the amino group can be converted to a substituted amino group by alkylation or the like by a general method.
[0136] 本発明の化合物（I)は、下記の [製造法 2]に示す、 [ルート A]又は [ルート B]でも 製造すること力 Sでさる。  [0136] The compound (I) of the present invention can be produced by [Route A] or [Route B] shown in [Production Method 2] below with the force S.
[製造法 2]  [Production method 2]
[0137] [化 28]  [0137] [Chemical 28]
[ルート A] [Route A]
Figure imgf000047_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000048_0001
[0139] (式中、環 A、
Figure imgf000048_0002
R2、 R2°a、 R2°b、 R21、 X及び Yは前記と同じものを示す。） [0139] (wherein ring A,
Figure imgf000048_0002
R 2 , R 2 ° a , R 2 ° b , R 21 , X and Y are the same as described above. )
[0140] [ルート A] [0140] [Route A]
一般式 (I)の化合物は、化合物（1)と有機ボロン酸誘導体（6)から、 [製造法 1 2] で示したカップリング反応で化合物（7a)を製造し、化合物（7a)から [製造法 1 2] で示した方法でカルボン酸誘導体である化合物（7b)を製造し、化合物（7b)とァミン 体（5)から、 [製造法 1 3]で示した縮合反応で化合物（8)を製造し、化合物（8)とァ ミン（2)から、 [製造法 1 1]で示した求核置換反応を準用して製造することができる The compound of the general formula (I) is produced from the compound (1) and the organic boronic acid derivative (6) by the coupling reaction shown in [Production method 12], and from the compound (7a) [ Compound (7b), which is a carboxylic acid derivative, is produced by the method shown in Production method 12], and compound (8b) is produced from compound (7b) and amine compound (5) by the condensation reaction shown in [Production method 13]. ), And can be produced from compound (8) and amine (2) by applying the nucleophilic substitution reaction shown in [Production Method 1 1].
〇 Yes
[0141] [ノレート B]  [0141] [Noreto B]
また、一般式 (I)の化合物は、カルボン酸誘導体である化合物（7b)とァミン（2)との 求核置換反応で化合物（4)を製造し、化合物（4)から、 [製造法 1 3]で示したアミ ン体（5)との縮合反応で製造することができる。  In addition, the compound of the general formula (I) is produced from the compound (4) by the nucleophilic substitution reaction between the carboxylic acid derivative compound (7b) and the amine (2). It can be produced by a condensation reaction with the amine body (5) shown in 3].
[0142] ここで、化合物（8)又は化合物（I)の基 Y上にアミノ基等の官能基を有する場合、当 該ァミノ基等の官能基は保護されていてもよぐ当該保護基の除去は前述のように一 般的に汎用される方法を用いればよい。更に、そのアミノ基は一般的な方法によりァ ルキル化等を行って、置換アミノ基に変換することができる。  [0142] Here, when a functional group such as an amino group is present on the group Y of the compound (8) or the compound (I), the functional group such as the amino group may be protected. For the removal, a generally used method may be used as described above. Further, the amino group can be converted to a substituted amino group by alkylation or the like by a general method.
[0143] [製造法 1]及び [製造法 2]で使用したアミン体（5)は、市販であるか、又は下記の [ 製造法 A—；！]〜 [製造法 A— 5]に示す方法で製造することができる。  [0143] The amine compound (5) used in [Production Method 1] and [Production Method 2] is commercially available, or the following [Production Method A—; ] To [Production method A-5].
[0144] アミン体（5)が、下記の式（5— a)  [0144] The amine compound (5) is represented by the following formula (5-a):
[0145] [化 30] -
Figure imgf000049_0001
[0145] [Chemical 30] -
Figure imgf000049_0001
[0146] [式中、 Aiaはメチレン基又はエチレン基（このメチレン基及びエチレン基は、同一又 は異なって、ハロゲノ基、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C；!〜 C6アルコキシ C1〜C6アルキル基、水酸基、 C1〜C6アルコキシ基、ハロゲノ C；!〜 C6アルコキシ基及び C1〜C6アルコキシ C1〜C6アルコキシ基からなる群より選ば れる基で 1〜4個置換されていてもよい。）を示し、 R3a、 R4a及び R5aは前記と同じもの を示す。 ]で表される化合物は、下記の [製造法 A— 1]で製造することができる。 [In the formula, A ia represents a methylene group or an ethylene group (the methylene group and the ethylene group are the same or different and are each a halogeno group, a C1-C6 anolenoquinol group, a halogeno C1-C6 alkyl group, C;!- C6-alkoxy C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C;! -C6 alkoxy group and C1-C6 alkoxy group are substituted with 1 to 4 groups selected from the group consisting of C1-C6 alkoxy groups R 3a , R 4a and R 5a are the same as described above. Can be produced by the following [Production Method A-1].
[製造法 A— 1]  [Production method A— 1]
[0147] [化 31]  [0147] [Chemical 31]
』¾ ¾
3a 3 a
I 0 (9a)  I 0 (9a)
PG N— τϋϊίΤ
Figure imgf000049_0002
 PG N— τϋϊίΤ
Figure imgf000049_0002
(9) C IO) (5-a)  (9) C IO) (5-a)
[0148] (式中、 PGは保護基を示し、 Ala、 R3a、 R4a及び R5aは前記と同じものを示す。） (Wherein PG represents a protecting group, and A la , R 3a , R 4a and R 5a represent the same as described above.)
[0149] ァミン（5— a)は、アルデヒド（9)とァミン体（9a)又はその塩とを、還元剤の存在下に 処理する、還元的ァミノ化反応により化合物（10)を製造し、次に化合物（10)を脱保 護して製造すること力 Sできる。上記アルデヒド（9)及び還元的ァミノ化反応に使用する アミン体（9a)又はその塩は、市販であるか、又は公知の方法で製造可能である。還 元的ァミノ化反応の参考文献としては、実験化学講座（第四版、 Vol. 20. 日本化学 会編、丸善株式会社）「有機合成 II：アルコール 'ァミン、 P300〜P302」等を挙げる こと力 Sでさる。 Amin (5-a) produces compound (10) by a reductive amination reaction in which aldehyde (9) and ammine (9a) or a salt thereof are treated in the presence of a reducing agent. Next, it is possible to manufacture by deprotecting compound (10). The aldehyde (9) and the amine body (9a) or a salt thereof used for the reductive amination reaction are commercially available or can be produced by a known method. As a reference for the reductive amination reaction, there is an experimental chemistry course (4th edition, Vol. 20, edited by Japan Chemical Society, Maruzen Co., Ltd.) "Organic Synthesis II: Alcohol 'Amin, P300-P302". Touch with force S.
アミン体（9a)又はその塩の使用量は、化合物（9)に対して 0. ；!〜 4倍モル当量の 範囲が好ましい。  The amount of the amine compound (9a) or salt thereof used is preferably in the range of 0.;! To 4 times molar equivalents relative to the compound (9).
還元剤としては、金属水素化物等が好ましぐ例えば水素化ホウ素ナトリウム、シァ ノ水素化ホウ素ナトリウム、トリァセトキシ水素化ホウ素ナトリウム等が好ましい。還元剤 の使用量は、化合物（9)に対して 0. 2〜4倍モル当量の範囲が好ましい。 As the reducing agent, metal hydrides are preferred, for example, sodium borohydride, Sodium borohydride, sodium triacetoxyborohydride and the like are preferable. The amount of the reducing agent used is preferably in the range of 0.2 to 4 molar equivalents relative to compound (9).
反応溶媒としては、反応を阻害せず、出発物質をある程度溶解するものであれば 特に制限はなぐトルエン、キシレン、ベンゼン、ヘプタン、へキサン等の炭化水素系 溶媒、クロ口ホルム、ジクロロメタン、 1 , 2—ジクロロェタン等のハロゲン化炭化水素系 溶媒、ジェチルエーテル、テトラヒドロフラン、 1； 4ージォキサン等のエーテル系溶媒 、メタノール、エタノール等のアルコール系溶媒、 N, N—ジメチルホルムアミド、 N- メチルー 2—ピロリドン等のアミド系溶媒、ジメチルスルホキシド等のスルホキシド系溶 媒、ァセトニトリル、水、酢酸等の極性溶媒等が好ましぐこれらの溶媒は、二種以上 の混合溶媒として使用してもよい。 The reaction solvent is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, etc., chloroform, dichloromethane, 1, Halogenated hydrocarbon solvents such as 2-dichloroethane, jetyl ether, tetrahydrofuran, 1 ; ether solvents such as 4-dioxane, alcohol solvents such as methanol and ethanol, N, N-dimethylformamide, N-methyl-2-pyrrolidone Such amide solvents, sulfoxide solvents such as dimethyl sulfoxide, polar solvents such as acetonitrile, water, and acetic acid are preferred. These solvents may be used as a mixture of two or more.
反応温度としては、 0°C〜溶媒の沸点の範囲であり、 20°C〜80°Cの範囲が好まし い。  The reaction temperature is in the range of 0 ° C to the boiling point of the solvent, preferably in the range of 20 ° C to 80 ° C.
反応時間は通常 1時間〜 3日程度である。  The reaction time is usually about 1 hour to 3 days.
[0150] アミン体（5)が、下記の式（5— b)  [0150] The amine compound (5) is represented by the following formula (5-b):
[0151] [化 32] [0151] [Chemical 32]
Figure imgf000050_0001
Figure imgf000050_0001
[0152] (式中、環 Bはシクロペンタン環又はシクロへキサン環を示し、 R4e、！Te、 R12e、 R13e、 R 14e、 k及び 1は前記と同じものを示す。）で表される化合物は、下記の [製造法 A— 2] で製造すること力できる。 [In the formula, ring B represents a cyclopentane ring or a cyclohexane ring, and R 4e,! T e , R 12e , R 13e , R 14e , k, and 1 represent the same as described above.] Can be produced by the following [Production Method A-2].
[製造法 A— 2]  [Production method A-2]
[0153] [化 33] [0153] [Chemical 33]
Figure imgf000051_0001
Figure imgf000051_0001
[0154] (式中、 PG、環 B、 R4\ R5\ R12\ R13c、 R14 k及び 1は前記と同じものを示す。） [Wherein, PG, ring B, R 4 \ R 5 \ R 12 \ R 13c , R 14 k and 1 are the same as defined above]
[0155] ァミン（5— b)は、ジァミン体（11)の一方のアミノ基を保護して化合物（12)を製造し 、化合物（12)を、一般的に汎用される塩基存在下でアルキル化剤と処理する、アル キル化反応を行うか、又は [製造法 A— 1 ]の還元的ァミノ化反応を準用して化合物（ 13)を製造し、化合物（13)を脱保護して製造することができる。アルキル化反応及び 還元的ァミノ化反応の参考文献としては、実験化学講座（第四版、 Vol. 20. 日本化 学会編、丸善株式会社）「有機合成 II：アルコール.ァミン、 P284〜P288及び P300 〜P302」等を挙げること力 Sできる。また、上記のジァミン体（11)は、巿販であるか、 又は公知の方法で製造することができる。 Amine (5-b) is a compound (12) produced by protecting one amino group of diamine body (11), and compound (12) is alkylated in the presence of a commonly used base. The compound (13) is produced by applying the alkylation reaction treated with an agent, or applying the reductive amination reaction of [Production method A-1], and deprotecting the compound (13). can do. References for the alkylation reaction and reductive amination reaction include the Experimental Chemistry Course (4th Edition, Vol. 20. The Chemical Society of Japan, Maruzen Co., Ltd.) “Organic Synthesis II: Alcohol. ~ P302 "etc. Power S In addition, the above-mentioned diamine (11) is commercially available or can be produced by a known method.
アルキル化に使用する塩基としては、トリェチルァミン、ジイソプロピルェチルァミン 、 N メチルモルホリン、ピリジン、 4— (N, N ジメチルァミノ）ピリジン等の有機アミ ン系塩基又は炭酸カリウム、炭酸セシウム等の無機塩基が好ましい。塩基の使用量と しては、化合物（12)に対して、 1〜30当量の範囲、好ましくは;!〜 10当量の範囲を 挙げること力 Sできる。反応時間は、通常 1〜48時間程度である。  Bases used for alkylation include organic amine bases such as triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, or inorganic bases such as potassium carbonate and cesium carbonate. preferable. The amount of the base used can be in the range of 1 to 30 equivalents, preferably in the range of !! to 10 equivalents, relative to the compound (12). The reaction time is usually about 1 to 48 hours.
アルキル化剤としては、市販又は公知の方法で製造可能な下記の式（12a)又は（12 b)  As the alkylating agent, the following formula (12a) or (12b) which can be produced commercially or by a known method:
[0156] [化 34]  [0156] [Chemical 34]
L R4c (12a) 、 LR 4c (12a),
L R5c (12b) [0157] (式中、 Lは脱離基を示し、 R4e及び R5eは前記と同じものを示す。）で表される化合物 を使用すること力できる。 LR 5c (12b) [0157] It is possible to use a compound represented by the formula (wherein L represents a leaving group, and R 4e and R 5e represent the same as described above).
[0158] 脱離基（Uとしては、例えばノヽロゲノ基、 C1〜C6アルキルスルホニルォキシ基、置 換基を有していてもよいフエニルスルホニルォキシ基等が挙げられ、臭素原子、ヨウ 素原子、メタンスルフォニルォキシ基、ベンゼンスルホニルォキシ基及び p トルエン スルホニルォキシ基等が好ましレ、。  [0158] The leaving group (U includes, for example, a neurogeno group, a C1-C6 alkylsulfonyloxy group, a phenylsulfonyloxy group which may have a substituent, and the like. Elementary atoms, methanesulfonyloxy groups, benzenesulfonyloxy groups and p-toluenesulfonyloxy groups are preferred.
アルキル化の反応溶媒としては、反応を阻害せず、出発物質をある程度溶解するも のであれば特に制限はなぐクロ口ホルム、ジロロメタン等のハロゲン化炭化水素系溶 媒、トルエン、ベンゼン等の炭化水素系溶媒、ジェチルエーテル、テトラヒドロフラン 等のエーテル系溶媒、メタノール、エタノール等のアルコール系溶媒、 N, N ジメチ ルホルムアミド等のアミド系溶媒、ァセトニトリル、水等の極性溶媒等が好ましぐこれ らの溶媒は、二種以上の混合溶媒として使用してもよい。  The reaction solvent for alkylation is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Halogenated hydrocarbon solvents such as chloroform and dichloromethane, and hydrocarbons such as toluene and benzene. Solvents such as organic solvents, ether solvents such as jetyl ether and tetrahydrofuran, alcohol solvents such as methanol and ethanol, amide solvents such as N and N dimethylformamide, polar solvents such as acetonitrile and water are preferred. You may use a solvent as a 2 or more types of mixed solvent.
反応温度としては、 20°C〜溶媒の沸点の範囲であり、室温〜 80°Cの範囲が好ま しい。  The reaction temperature is in the range of 20 ° C to the boiling point of the solvent, preferably in the range of room temperature to 80 ° C.
反応時間は通常 1〜48時間程度である。  The reaction time is usually about 1 to 48 hours.
[0159] アミン体（5)が、下記の式（5— c 1 )  [0159] The amine compound (5) is represented by the following formula (5-c 1):
[0160] [化 35] [0160] [Chemical 35]
Figure imgf000052_0001
Figure imgf000052_0001
[0161] (式中、 rは 0又は 1を示し、 R3g、 R4g、 R12g、 R1 及び R14gは前記と同じものを示す。 [Wherein r represents 0 or 1, and R 3g , R 4g , R 12g , R 1 and R 14g represent the same as described above.
で表される化合物は、下記の [製造法 A— 3]で製造すること力 Sできる。  Can be produced by the following [Production Method A-3].
[製造法 A— 3]  [Production method A-3]
[0162] [化 36]
Figure imgf000053_0001
[0162] [Chemical 36]
Figure imgf000053_0001
(17) (5-c-D  (17) (5-c-D
[0163] (式中、 PG1及び PG2は保護基を示し、 r、 R 、 R4\ R1 、 R1 及び R14gは前記と同じ ものを示す。） [In the formula, PG 1 and PG 2 represent protecting groups, and r, R, R 4 \ R 1 , R 1 and R 14g represent the same as described above.]
[0164] ァミン（5— c 1)は、市販又は公知の方法で製造可能な化合物（14)のアミノ基を 保護して化合物（15)を製造し、化合物（15)を、選択的脱保護反応にて化合物（16 )を製造し、化合物（16)をアルキル化反応又は還元的ァミノ化反応で化合物（17)を 製造し、化合物（17)を脱保護して製造することができる。アルキル化反応及び還元 的ァミノ化反応の参考文献としては、実験化学講座 (第四版、 Vol. 20. 日本化学会 編、丸善株式会社）「有機合成 II：アルコール 'ァミン、 P284〜P288及び P300〜P 302」等を挙げること力 Sできる。  [0164] Amine (5-c 1) is produced by protecting compound (14), which is commercially available or can be produced by a known method, to produce compound (15), and selectively deprotecting compound (15) Compound (16) can be produced by the reaction, compound (16) can be produced by alkylation reaction or reductive amination reaction, compound (17) can be produced, and compound (17) can be deprotected. References for alkylation reactions and reductive amination reactions include the Experimental Chemistry Course (4th edition, Vol. 20. Edited by the Chemical Society of Japan, Maruzen Co., Ltd.) “Organic Synthesis II: Alcohol 'Amin, P284-P288 and P300. ~ P 302 "etc. Power S
[0165] アミン体（5)が、下記の式（5— c 2)  [0165] The amine compound (5) is represented by the following formula (5-c 2)
[0166] [化 37]  [0166] [Chemical 37]
Figure imgf000053_0002
Figure imgf000053_0002
[0167] (式中、 R4e、 R"e、 R"e、 R14e及び oは前記と同じものを示す。）で表される化合物は、 下記の [製造法 A— 4]で製造することができる。 [製造法 A [0167] The compound represented by the formula (wherein R 4e , R " e , R" e , R 14e and o are as defined above) is produced by the following [Production Method A-4]. be able to. [Production method A
[0168] [化 38][0168] [Chemical 38]
Figure imgf000054_0001
Figure imgf000054_0001
[0169] (式中、 R は、水素原子、 C1〜C6ァノレキノレ基、置換基を有していてもよいフエニル 基又は置換基を有していてもよいベンジル基を示し、 R23は、メチル基、ハロゲノメチ ル基、置換基を有してレ、てもよ!/、フエニル基又は置換基を有して!/、てもよ!/、ベンジル 基を示し、 R4e、 R12e、 R13e、 R14e及び oは前記と同じものを示す。 ) (Wherein R 1 represents a hydrogen atom, a C1-C6 anolenoquinole group, an optionally substituted phenyl group or an optionally substituted benzyl group, and R 23 represents a methyl group. A group, a halogenomethyl group, having a substituent, may be! /, Having a phenyl group or a substituent! /, May! /, A benzyl group, R 4e , R 12e , R 13e , R 14e and o are the same as above.)
[0170] ァミン（5— c— 2)は、化合物（18)を還元しアルコール体（19)を製造し、アルコー ル体（19)をスルホニル化して化合物（20)を製造し、化合物（20)をアジド化して化 合物（21)を製造し、化合物（21)を還元して製造することができる。  Amine (5-c-2) is prepared by reducing compound (18) to produce alcohol (19), and sulfonylating alcohol (19) to produce compound (20). ) Can be produced by azidating to produce compound (21) and reducing compound (21).
カルボキシ基又はそのエステル基の還元反応の参考文献としては、実験化学講座（ 第四版、 Vol. 20. 日本化学会編、丸善株式会社）「有機合成 II：アルコール 'ァミン、 P10-P14J等を挙げること力 Sできる。  As a reference for the reduction reaction of the carboxy group or its ester group, please refer to Experimental Chemistry Course (4th edition, Vol. 20, edited by The Chemical Society of Japan, Maruzen Co., Ltd.) “Organic Synthesis II: Alcohol 'Amin” The power to raise S.
水酸基のスルホニル化の参考文献としては、実験化学講座（第四版、 Vol. 24. 日 本化学会編、丸善株式会社）「有機合成 VI：ヘテロ元素 ·典型金属元素化合物、 P3 94〜P396」等を挙げること力 Sできる。スルホニル基のアジド基への変換反応の参考 文献としては、実験化学講座 (第四版、 Vol. 20. 日本化学会編、丸善株式会社）「 有機合成 II：アルコール 'ァミン、 P415〜P420」等を挙げることができる。  As a reference for sulfonylation of hydroxyl group, Experimental Chemistry Course (4th edition, Vol. 24, edited by The Chemical Society of Japan, Maruzen Co., Ltd.) “Organic synthesis VI: Heteroelements ・ Typical metal element compounds, P3 94-P396” It is possible to give power S. References for the conversion reaction of sulfonyl group to azide group include experimental chemistry course (4th edition, Vol. 20, edited by Chemical Society of Japan, Maruzen Co., Ltd.) “Organic synthesis II: Alcohol 'Amin, P415 ～ P420” etc. Can be mentioned.
アジド基のアミノ基への還元反応の参考文献としては、実験化学講座（第四版、 Vo 1. 20. 日本化学会編、丸善株式会社）「有機合成 II :アルコール 'ァミン、 P279〜P2References for the reduction reaction of an azide group to an amino group include an experimental chemistry course (4th edition, Vo 1. 20. The Chemical Society of Japan, Maruzen Co., Ltd.) “Organic Synthesis II: Alcohol 'Amin, P279 ～ P2
82」等を挙げること力 Sできる。 82 ”and so on.
[0171] アミン体（5)が、下記の式（5— d— 1)又は（5— d— 2)  [0171] The amine compound (5) is represented by the following formula (5-d-1) or (5-d-2):
[0172] [化 39] [0172] [Chemical 39]
Figure imgf000055_0001
Figure imgf000055_0001
(5-d-l ) (5 - d - 2)  (5-d-l) (5-d-2)
[0173] (式中、 sは 1又は 2の整数を示し、 R4h、 Rbh、 R1 , R10 R14h及び ρは前記と同じもの を示す。）で表される化合物は、下記の [製造法 Α— 5]に示すように製造することがで きる。 [0173] (wherein, s represents an integer of 1 or 2, R 4h , R bh , R 1 , R 10 R 14h and ρ represent the same as described above), It can be manufactured as shown in [Manufacturing method Α-5].
[製造法 A— 5]  [Production method A-5]
[0174] [化 40] [0174] [Chemical 40]
Figure imgf000055_0002
Figure imgf000055_0002
(22a) (24a) (5-d-  (22a) (24a) (5-d-
Figure imgf000055_0003
Figure imgf000055_0003
(22b) (24b) (5 d 2)  (22b) (24b) (5 d 2)
[0175] (式中、 PG、 R4h、 R5h、 R12h、 R13h、 R14h、 p及び sは前記と同じものを示す。 ) [In the formula, PG, R 4h , R 5h , R 12h , R 13h , R 14h , p and s are the same as described above.]
[0176] ァミン（5— d—l又は 5— d— 2)は、アルデヒド（22a)又はケトン（22b)を、アミン体（ [0176] Amine (5-dl or 5-dl-2) is an aldehyde (22a) or ketone (22b)
23)又はその塩と、還元剤で処理する、還元的ァミノ化反応により化合物（24a)又は 化合物（24b)を製造し、化合物（24a又は 24b)を脱保護して製造することができる。 上記のアルデヒド（22a)、ケトン（22b)及びアミン体（23)は、巿販であるか、又は公 知の方法で製造することができる。還元的ァミノ化反応の参考文献としては、実験化 学講座（第四版、 Vol. 20. 日本化学会編、丸善株式会社）「有機合成 II：アルコール .ァミン、 P300〜P302」等を挙げ、ることカできる。 23) or a salt thereof and a compound (24a) or Compound (24b) can be produced, and compound (24a or 24b) can be produced by deprotection. The aldehyde (22a), ketone (22b) and amine body (23) are commercially available or can be produced by known methods. References for reductive amination reactions include experimental chemical courses (4th edition, Vol. 20, edited by The Chemical Society of Japan, Maruzen Co., Ltd.) “Organic Synthesis II: Alcohol. Amines, P300-P302”, etc. I can do it.
アミン体（5)が、下記の式（5— e— 1)  The amine body (5) is represented by the following formula (5-e-1)
[化 41][Chemical 41]
Figure imgf000056_0001
Figure imgf000056_0001
(5-e-1 )  (5-e-1)
(式中、 q、 V、 Rd R1 , Rldv及び R14vは前記と同じものを示す。）で表される化合物 は、下記の [製造法 A— 6]に示すように製造すること力 Sできる。 (Wherein, q, V, R d R 1, R ldv and R 14v is. Of the same meanings as defined above) compound represented by the be prepared as shown in [Production Method A- 6] below Power S can be.
[製造法 A— 6]  [Production method A-6]
[化 42]
Figure imgf000056_0002
[Chemical 42]
Figure imgf000056_0002
(28) (5十 1 )  (28) (50 1)
(式中、 q、 V、 R3v、 R12v、 R13v、 R14v、 R22及び R23は前記と同じものを示す。） ァミン（5— e— 1)は、公知の方法で合成したモルホリン環を有するカルボン酸エス テル（25)を、製造法 A— 4に記載の合成ルートと同様の操作を行い、合成することが できる。 [0177] 上記の方法で製造された本発明化合物 (I)は、公知の方法、例えば、抽出、沈殿、 蒸留、クロマトグラフィー、分別再結晶、再結晶等により単離、精製すること力 Sできる。 また、本発明化合物 (I)又は製造の中間体が不斉炭素を有する場合には光学異性 体が存在する。これらの光学異性体は、適切な塩と再結晶する分別再結晶 (塩分割） やカラムクロマトグラフィー等の常法によって、それぞれの異性体を単離、精製するこ とができる。ラセミ体から光学異性体を分割する方法の参考文献としては、 J. Jacque sらの、 「Enantiomers , Racemates and Resolution, John Wiley Ana Son s , Inc.」を挙げることカできる。 (Wherein, q, V, R 3v, R 12v, R 13v, R 14v, R 22 and R 23 have the same meanings as defined above.) Amin (5-e- 1) was synthesized by a known method Carboxylic acid ester (25) having a morpholine ring can be synthesized by the same operation as the synthesis route described in Production method A-4. [0177] The compound (I) of the present invention produced by the above method can be isolated and purified by a known method such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization and the like. . Further, when the compound (I) of the present invention or the intermediate of production has an asymmetric carbon, an optical isomer exists. These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) recrystallizing with an appropriate salt and column chromatography. As a reference for a method for resolving an optical isomer from a racemate, “Enantiomers, Racemates and Resolution, John Wiley Ana Sons, Inc.” by J. Jacques et al.
[0178] 前述のとおり、 TNF - a産生抑制剤は慢性関節リウマチ等の各種炎症性疾患又 は自己免疫疾患等の治療薬として有用である。  [0178] As described above, TNF-a production inhibitors are useful as therapeutic agents for various inflammatory diseases such as rheumatoid arthritis or autoimmune diseases.
[0179] 炎症性疾患としては、例えば慢性関節リウマチ、リウマチ性脊椎炎、骨関節炎、喘 息、気管支炎、アレルギー性鼻炎、慢性閉塞性肺疾患、嚢胞性繊維症、炎症性腸疾 患、過敏性腸症候群、粘液性大腸炎、潰瘍性大腸炎、クローン病、多発性硬化症等 を挙げること力 Sでさる。  [0179] Examples of inflammatory diseases include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, asthma, bronchitis, allergic rhinitis, chronic obstructive pulmonary disease, cystic fibrosis, inflammatory bowel disease, irritability To mention genital bowel syndrome, mucinous colitis, ulcerative colitis, Crohn's disease, multiple sclerosis, etc.
[0180] 自己免疫性疾患としては、例えば膠原病、全身性エリテマトーデス、慢性関節リウ マチ、脊椎炎、骨関節症、通風、敗血症、敗血症ショック（septic shock)、毒性ショ ック症候群、アトピー性皮膚炎、接触皮膚炎、多発性硬化症、ベーチェット病、ネフ口 ーゼ症候群、ループス腎炎、糸球体腎炎、シユーダレン症候群、紅斑性狼瘡、力へ キシ一、強皮症、多発性筋炎、乾癬、炎症性腸疾患、クローン病、混合型結合組織 病、慢性閉鎖性肺病、滞留性心停止、肺繊維症、原発性粘液水腫、アジソン病、再 生不良性貧血、 自己免疫性溶血性貧血、自己免疫性血小板減少症、自己免疫性 糖尿病、インスリン抵抗性 (insulin resistance)、ブドウ膜炎、抗受容体病、重症筋 無力症、甲状腺中毒症、甲状腺炎、橋本病、ウィルス感染、 AIDS等が挙げられる。  [0180] Examples of autoimmune diseases include collagen disease, systemic lupus erythematosus, rheumatoid arthritis, spondylitis, osteoarthritis, ventilation, sepsis, septic shock, toxic shock syndrome, and atopic skin. Inflammation, contact dermatitis, multiple sclerosis, Behcet's disease, nephew syndrome, lupus nephritis, glomerulonephritis, Syudalen syndrome, lupus erythematosus, force hex, scleroderma, polymyositis, psoriasis, inflammation Enteric disease, Crohn's disease, mixed connective tissue disease, chronic obstructive pulmonary disease, retention cardiac arrest, pulmonary fibrosis, primary myxedema, Addison's disease, aplastic anemia, autoimmune hemolytic anemia, autoimmunity Thrombocytopenia, autoimmune diabetes, insulin resistance, uveitis, antireceptor disease, myasthenia gravis, thyroid poisoning, thyroiditis, Hashimoto's disease, viral infection, AIDS, etc. The
[0181] 一般式 (I)で表される本発明の化合物、その塩又はそれらの溶媒和物を哺乳動物（ 特にヒト）に投与する場合には、全身的又は局所的に、経口又は非経口で投与する こと力 Sでさる。  [0181] When the compound of the present invention represented by the general formula (I), a salt thereof, or a solvate thereof is administered to a mammal (particularly a human), systemically or locally, orally or parenterally Dosing with a force S
[0182] 本発明の医薬は、投与方法に応じて適当な形態を選択し、通常用いられている各 種製剤の調製法によって製造できる。 [0183] 経口用の医薬の形態としては、錠剤、丸剤、散剤、顆粒剤、カプセル剤、水剤、懸 濁剤、乳剤、シロップ剤、エリキシル剤等が挙げられる。これら形態の医薬の調製は、 添加剤として通常用いられている賦形剤、結合剤、崩壊剤、滑沢剤、膨潤剤、膨潤 補助剤、コーティング剤、可塑剤、安定剤、防腐剤、抗酸化剤、着色剤、溶解補助剤 、懸濁化剤、乳化剤、甘味剤、保存剤、緩衝剤、希釈剤、湿潤剤等から必要に応じ て適宜選択したものを用いて、常法に従って行うことができる。 [0182] The medicament of the present invention can be produced by selecting an appropriate form according to the administration method and preparing various preparations usually used. [0183] Examples of the pharmaceutical form for oral use include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like. The preparation of these forms of pharmaceuticals consists of excipients, binders, disintegrants, lubricants, swelling agents, swelling aids, coating agents, plasticizers, stabilizers, antiseptics, antiseptics commonly used as additives. Use an oxidizing agent, a coloring agent, a solubilizing agent, a suspending agent, an emulsifier, a sweetener, a preservative, a buffering agent, a diluent, a wetting agent, etc. Can do.
[0184] 非経口用の医薬の形態としては、注射剤、軟膏剤、ゲル剤、クリーム剤、湿布剤、 貼付剤、噴霧剤、吸入剤、スプレー剤、点眼剤、点鼻剤、座剤、吸入剤等が挙げられ る。これら形態の医薬の調製は、添加剤として通常用いられている安定化剤、防腐剤 、溶解補助剤、保湿剤、保存剤、抗酸化剤、着香剤、ゲル化剤、中和剤、溶解補助 剤、緩衝剤、等張剤、界面活性剤、着色剤、緩衝化剤、増粘剤、湿潤剤、充填剤、 吸収促進剤、懸濁化剤、結合剤等から必要に応じて適宜選択したものを用いて、常 法に従って行うことができる。  [0184] Pharmaceutical forms for parenteral use include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, And inhalants. The preparation of these forms of pharmaceuticals includes stabilizers, preservatives, solubilizers, moisturizers, preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, dissolution agents that are commonly used as additives. Adjuvant, buffer, isotonic agent, surfactant, colorant, buffer, thickener, wetting agent, filler, absorption enhancer, suspending agent, binder, etc. Can be carried out according to a conventional method.
[0185] 本発明の医薬は、一般式 (I)で表される化合物、その塩又はそれらの溶媒和物と、 免疫抑制剤、免疫抑制に用いる抗体、拒絶反応治療薬、抗生物質、非ステロイド性 抗炎症薬 (NSAIDs)及びステロイド薬から選択される 1種又は 2種以上を組み合わ せてなる医薬としてもよい。この医薬は、一般式 (I)で表される本発明の化合物、その 塩又はそれらの溶媒和物と、他の薬剤の 1種又は 2種以上とを組み合わせて併用剤 として投与されるものであり、一般式 (I)で表される本発明の化合物、その塩又はそれ らの溶媒和物と他の薬剤との併用剤は、 1つの製剤中に両成分が配合された合剤と してもよく、別々の製剤として投与されるものでもよい。別々に投与される場合、それ ぞれの製剤は同時に投与してもよぐ時間差をおいて投与してもよい。また、それぞ れの製剤の投与方法は同じであってもよいし、異なっていてもよい。これらの医薬は、 一般式 (I)で表される化合物、その塩又はそれらの溶媒和物と、免疫抑制剤、免疫 抑制に用いる抗体、拒絶反応治療薬、抗生物質、非ステロイド性抗炎症薬 (NSAID s)及びステロイド薬から選択される 1種又は 2種以上等の他の薬剤とを組み合わせた キッ卜としてもよい。  [0185] The medicament of the present invention comprises a compound represented by the general formula (I), a salt thereof or a solvate thereof, an immunosuppressant, an antibody used for immunosuppression, a therapeutic agent for rejection, an antibiotic, a nonsteroid It may be a pharmaceutical comprising one or more selected from sex anti-inflammatory drugs (NSAIDs) and steroid drugs. This medicament is administered as a combination drug by combining the compound of the present invention represented by the general formula (I), a salt thereof or a solvate thereof and one or more of other drugs. The combination of the compound of the present invention represented by the general formula (I), a salt thereof or a solvate thereof and another drug is a combination of both components in one preparation. It may be administered as a separate formulation. When administered separately, each preparation may be administered at the same time or at a time difference. Moreover, the administration method of each preparation may be the same or different. These medicines include compounds represented by general formula (I), salts thereof or solvates thereof, immunosuppressants, antibodies used for immunosuppression, rejection drugs, antibiotics, nonsteroidal anti-inflammatory drugs. It may be a kit that combines (NSAIDs) and other drugs such as one or more selected from steroid drugs.
より具体的には、免疫抑制剤、免疫抑制に用いる抗体、拒絶反応治療薬としては、 例えばシクロスポリン八、タクロリムス（FK506)、シロリムス（ラパマイシン）、ァザチォ プリン、ミゾリビン、メトトレキサート、ミコフエノール酸モフエチル、シクロホスフアミド、シ ロリムス、エベロリムス、プレドニゾロン、メチノレプレドニゾロン、オノレソクローン OKT3、 抗ヒトリンパ球グロブリン、デォキシスパーガリン、エタネルセブト、インフリキシマブ又 はリツキサン等が挙げられる。 More specifically, as an immunosuppressant, an antibody used for immunosuppression, and a rejection treatment, For example, cyclosporine 8, tacrolimus (FK506), sirolimus (rapamycin), azathioprine, mizoribine, methotrexate, mycophenolate mofuethyl, cyclophosphamide, sirolimus, everolimus, prednisolone, methinoreprednisolone, onoleclone OKT globulin , Deoxyspargarine, etanercebut, infliximab or rituxan.
[0186] 抗生物質としては、例えばセフロキシムナトリウム、メロぺネム三水和物、硫酸ネチ ルマイシン、硫酸シソマイシン、セフチブテン、 ΡΑ— 1806、 IB— 367、トブラマイシ ン、 PA— 1420、ドキソルビシン、硫酸ァストロマイシン、塩酸セフエタメトピボキシル 等が挙げられる。 [0186] Antibiotics include, for example, cefuroxime sodium, meropenem trihydrate, netilmycin sulfate, sisomycin, ceftibutene, ΡΑ-1806, IB-367, tobramycin, PA-1420, doxorubicin, astrol sulfate Mycin, ceftametopivoxil hydrochloride, and the like.
[0187] 非ステロイド性抗炎症薬（NSAIDs)としては、例えばアスピリン、サリチル酸、ジクロ フエナク、インドメタシン、イブプロフェン、ケトプロフェン、ロキソプロフェン、ナプロキ セン、ピロキシカム、メロキシマク、ァセクロフエナク、ァクタリット、ジァセレイン、エトド ラタ、セレコキシブ、ノレミラコキシブ等を挙げることができる。  [0187] Non-steroidal anti-inflammatory drugs (NSAIDs) include, for example, aspirin, salicylic acid, diclofenac, indomethacin, ibuprofen, ketoprofen, loxoprofen, naproxen, piroxicam, meloximac, aceclofenac, actarito, dicereine, Etc.
[0188] ステロイド薬としては、例えばプロピオン酸クロべタゾール、酢酸ジフロラゾン、フル オシノニド、フランカルボン酸モメタゾン、ジプロピオン酸ベタメタゾン、酪酸プロピオ ン酸ベタメタゾン、吉草酸ベタメタゾン、ジフルプレドナート、ブデソニド、吉草酸ジフ ルコルトロン、アムシノニド、ハルシノニド、デキサメタゾン、プロピオン酸デキサメタゾ ン、吉草酸デキサメタゾン、酢酸デキサメタゾン、酢酸ヒドロコルチゾン、酪酸ヒドロコ ノレチゾン、酪酸プロピオン酸ヒドロコルチゾン、プロピオン酸デプロドン、吉草酸酢酸 プレドニゾロン、フルオシノロンァセトニド、プロピオン酸べクロメタゾン、トリアムシノロ ンァセトニド、ピバル酸フルメタゾン、プロピオン酸アルクロメタゾン、酪酸クロべタゾン 、プレドニゾロン、プロピオン酸ぺクロメタゾン、フルドロキシコルチド、酢酸コルチゾン 、ヒドロコルチゾン、リン酸ヒドロコルチゾンナトリウム、コハク酸ヒドロコルチゾンナトリウ ム、酢酸フルド口コルチゾン、酢酸プレドニゾロン、コハク酸プレドニゾロンナトリウム、 ブチル酢酸プレドニゾロン、リン酸プレドニゾロンナトリウム、酢酸ハロプレドン、メチル プレドニゾロン、酢酸メチルプレドニゾロン、コハク酸メチルプレドニゾロンナトリウム、ト リアムシノロン、酢酸トリアムシノロン、リン酸デキサメタゾンナトリウム、パルミチン酸デ キサメタゾン、酢酸パラメサゾン、ベタメタゾン、プロピオン酸フルチ力ゾン、フルニソリ ド、 ST— 126P、シクレソニド、デキサメタゾンパロミチオネート、モメタゾンフランカノレ ボネート、プラステロンスルホネート、デフラザコート、メチルプレドニゾロンスレプタネ ート、メチルプレドニゾロンナトリウムスクシネート等が挙げられる。 [0188] Examples of steroid drugs include clobetasol propionate, diflorazone acetate, fluoconide, mometasone furanate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, budesonide, diph Lucortron, amsinonide, harsinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydroconorethione butyrate, hydrocortisone butyrate propionate, deprodon propionate, prednisolone acetic acid prednisolone, fluosinolone Beclomethasone, triamcinolone acetonide, flumethasone pivalate, alcromethasone propionate, clobetasone butyrate, predoni Ron, peclomethasone propionate, fludroxycortide, cortisone acetate, hydrocortisone, sodium hydrocortisone phosphate, hydrocortisone sodium succinate, flucortisone acetate, prednisolone acetate, prednisolone succinate, sodium prednisolone butyl acetate, prednisolone sodium phosphate, Halopredone acetate, methyl prednisolone acetate, methyl prednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, paramethasone acetate, betamethasone, flutizone propionate, flunisoli ST-126P, ciclesonide, dexamethasone paromithionate, mometasone francanorebonate, plasterone sulfonate, deflazacoat, methylprednisolone streptanate, methylprednisolone sodium succinate, and the like.
[0189] 一般式 (I)で表される本発明の化合物、その塩又はそれらの溶媒和物の投与量は 、症状、年齢、体重、組み合わせて投与する薬剤の種類や投与量等によって異なる 1S 通常、化合物（I)換算量で、成人一人一回につき 0. OOlmg〜； !OOOmgの範囲 で、全身的又は局所的に、一日一回から数回、経口又は非経口投与されるか、或い は一日 1時間〜 24時間の範囲で静脈内に持続投与されるのが好ましい。  [0189] The dose of the compound of the present invention represented by the general formula (I), a salt thereof, or a solvate thereof varies depending on symptoms, age, body weight, type of drug administered in combination, dose, etc. In general, in the amount of Compound (I) per adult, from 0.OOlmg to! OOOmg, systemically or locally, administered once or several times a day, orally or parenterally, Or it is preferably administered intravenously in the range of 1 to 24 hours per day.
[0190] 本発明化合物を含有する医薬は、化合物として成人 1人 1日当たり 1回を投与し、 適当な間隔で繰り返すのが望ましい。投与量は 0. 01mg〜2000mgの範囲、好まし <は 0. lmg〜； !OOOmgの範囲、より好まし <は lmg〜500mgである。  [0190] The pharmaceutical containing the compound of the present invention is preferably administered as a compound once a day for an adult and repeated at appropriate intervals. The dosage is in the range of 0.01 mg to 2000 mg, preferably <0.1 mg to;! OOOmg in the range, more preferably <mg to 500 mg.
[0191] さらに、本発明の医薬には、本発明の効果を損なわない範囲において、必要に応 じ、慢性関節リウマチ薬、抗乾癬薬、気管支拡張薬、抗気管支喘息薬又は抗糖尿病 薬を併用して用いることができる。  [0191] Further, the medicament of the present invention is used in combination with rheumatoid arthritis drugs, anti-psoriatic drugs, bronchodilators, anti-bronchial asthma drugs or antidiabetic drugs, as long as the effects of the present invention are not impaired. Can be used.
[0192] 本発明には、本発明化合物又はその塩を投与することを特徴とする前記疾患の防 止方法及び/又は治療方法も含まれる。  [0192] The present invention also includes a method for preventing and / or treating the aforementioned disease, which comprises administering the compound of the present invention or a salt thereof.
[0193] さらに、本発明には、前記医薬を製造するための本発明化合物、その塩又はそれ らの溶媒和物の使用も含まれる。 実施例  [0193] Furthermore, the present invention also includes use of the compound of the present invention, a salt thereof, or a solvate thereof for producing the aforementioned medicament. Example
[0194] 次に、実施例を挙げて本発明を詳細に説明するが、本発明はこれに限定されるも のではない。  [0194] Next, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.
[0195] 赤外スぺクトノレ（IR)は、 Hitachi 270— 30 spectrometer又は Horiba FT— 7 20 (S. T. Japan Durascope (Diamond/KRS— 5)を用い、 KBr打錠法或いは ATR法で測定した。元素分析は Perkin— Elmer CHNS/O 2400 (II)、 MITS UBISHI CHEMICAL XS— 100、或いは DIONEX DX— 320にて測定を行つ た。質量（MS)分析は JEOL JMS -AX505W (EI, FAB, CI)、 JEOL JMS— 70 0 (EI, FAB, FD, CI)、 Agilent Thechnologies Agilent 1100 series LC /MSD、 PE SCIEX API150EX (ESI)及び Micromass LCT (FAB)、或いは JMS -T100LP AccuTOF LC— plusを用いた。融点は Yanagimoto micro融 点測定器を用い、値は全て未補正である。核磁気共鳴スぺクトノレ (NMR)は JEOL J NM— EX400を用 V、て測定し、特に表示のなレ、場合はプロトン NMR — NMR) を意味し、内部標準としてテトラメチルシランを使用した。また、 ifi— NMRにおける 多重度は、 s = singlet、 d = doublet、 t = triplet、 q = quartet、 m = multiplet、及 び br s = broad singletを意味する。カラムクロマトグラフィーに用いたシリカゲルは 、 E— Merck社の Kiesel— gel 60 (particle size 0. 060— 0. 200mm)を用い た。また、薄層クロマトグラフィー（TLC)のプレートは E— Merck社製の Kieselgel60 F を使用した。 [0195] Infrared spectrum (IR) was measured by KBr tableting method or ATR method using Hitachi 270-30 spectrometer or Horiba FT-720 (ST Japan Durascope (Diamond / KRS-5)). Analysis was performed with Perkin—Elmer CHNS / O 2400 (II), MITS UBISHI CHEMICAL XS—100, or DIONEX DX—320, and mass (MS) analysis was performed using JEOL JMS-AX505W (EI, FAB, CI). , JEOL JMS— 70 0 (EI, FAB, FD, CI), Agilent Thechnologies Agilent 1100 series LC / MSD, PE SCIEX API150EX (ESI) and Micromass LCT (FAB), or JMS-T100LP AccuTOF LC—plus was used. Melting points were measured using a Yanagimoto micro melting point measuring instrument, and all values were uncorrected. Nuclear magnetic resonance spectroscopy (NMR) was measured using a JEOL J NM—EX400 V, and in particular, “reaction”, in the case of proton NMR—NMR), means tetramethylsilane as an internal standard. The multiplicity in ifi—NMR means s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br s = broad singlet. The silica gel used for column chromatography was Kiesel-gel 60 (particle size 0.060-0.200 mm) from E-Merck. As a thin layer chromatography (TLC) plate, Kieselgel 60 F manufactured by E-Merck was used.
254  254
また、本明細書では以下の略語を使用した。  Moreover, the following abbreviations were used in this specification.
[表 1] [table 1]
BH3 - DMS ポランジメチルスルフィ ド錯体 BH 3 -DMS Polanedimethylsulfide complex
B o c t e r t—ブトキシカルポニル  B o c t e r t-butoxycarbonyl
B o c 20 ジ— t e r t—ブチル ジカルボナ一ト B oc 2 0 Di-tert-butyl dicarbonate
B n ベンジル  B n benzyl
Cb z ベンジルォキシカルポニル  Cb z benzyloxycarbonyl
Z ベンジルォキシカルボニル  Z Benzyloxycarbonyl
CDC 13 重クロ口ホルム  CDC 13 heavy black mouth form
CD3OD 重メタノール CD 3 OD Heavy methanol
DM S 0- d 6 ジメチルスルホキシドー d6 DM S 0- d 6 Dimethylsulfoxide d 6
D I EA ジィソプロピルェチルァミン  D I EA diisopropylethylamine
DMAP 4— (N, N—ジメチルァミノ） ピリジン  DMAP 4— (N, N-dimethylamino) pyridine
DMF N, N ジメチルホルムアミド  DMF N, N Dimethylformamide
DMSO ジメチルスルホキシド  DMSO Dimethyl sulfoxide
EDC 1—ェチルー 3— （3—ジメチルァミノプロピル） カル ポジイミド 塩酸塩  EDC 1-Ethyl 3- (3-Dimethylaminopropyl) carbopositimide hydrochloride
HOB t 1ーヒドロキシベンゾトリアゾール  HOB t 1-hydroxybenzotriazole
M s メタンスルホニル  M s Methanesulfonyl
' B u t e r t—ブチル  'B u t e r t—Butyl
i p j. イソプロピル  i p j. Isopropyl
TEA トリェチルァミン  TEA Triethylamine
d p p f 1 , 1 ' —ビス （ジフエニルホスフイノ） フエロセ ン  d p p f 1, 1 '—bis (diphenylphosphino) ferrocene
[PdC 12 (dpp f) ] [1 , 1 ' —ビス （ジフエニルホスフイノ） フエ口 セン] ジクロロパラジウム （ I I ) [PdC 1 2 (dpp f)] [1, 1 '—Bis (diphenylphosphino) phenocene] dichloropalladium (II)
THF テトラヒドロフラン  THF tetrahydrofuran
TL C 薄層クロマトグラフィー  TL C thin layer chromatography
HPLC 高速液体クロマトグラフィー  HPLC HPLC
BOP ベンゾトリアゾール— 1 _ィルォキシトリス （ジメ チルァミノ） ホスホニゥム へキサフルォロホスフ エート  BOP Benzotriazole— 1_yloxytris (dimethylamino) phosphonium hexafluorophosphate
[0197] [参考例 1] 3 ブロモー 6 クロロイミダゾ [1, 2- (工程 1 ) 6 クロロイミダゾ [ 1 , 2— b]ピリダジン [0197] [Reference Example 1] 3 Bromo-6 chloroimidazo [1, 2- (Step 1) 6 Chloroimidazo [1, 2-b] pyridazine
[0198] [化 43]
Figure imgf000062_0001
ブロモアセトアルデヒド ジェチルァセタール（260ml, 1. 73mol)、 47%昊化水素 水（65ml)及び水（65ml)の混合物を、加熱還流下に 2時間攪拌下した。反応混合 液を室温に冷却後、 1, 2 ジメトキシェタン（2000ml)に注ぎ込んだ。混合液に炭酸 水素ナトリウム（粉末）を、発泡が治まるまで加えた。生成した不溶物をセライトを用い たろ過で除去した。ろ液に、 3—アミノー 6—クロ口ピリダジン（107g, 0. 826mol)を 加え、室温で 3日間攪拌した。反応液を、約半量になるまで減圧濃縮した。生成した 沈殿物を吸引ろ過でろ取し、これを 1 , 2—ジメトキシェタン及びエーテルで洗浄して 結晶性粉末を得た。得られた結晶性粉末を飽和炭酸水素ナトリウム水溶液（1200ml )に加え、発泡が治まるまで激しく攪拌した。沈殿物を減圧下にろ過でろ取し、飽和 炭酸水素ナトリウム水溶液及び水で洗浄した。得られた固形物を減圧下乾燥して標 記化合物（94. Og, 74%)を得た。 [0198] [Chemical 43]
Figure imgf000062_0001
A mixture of bromoacetaldehyde jetylacetal (260 ml, 1.73 mol), 47% aqueous hydrogen hydride (65 ml) and water (65 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was cooled to room temperature and poured into 1,2 dimethoxyethane (2000 ml). Carbonate into the mixture Sodium hydride (powder) was added until foaming subsided. The generated insoluble matter was removed by filtration using celite. To the filtrate, 3-amino-6-clopyridazine (107 g, 0.826 mol) was added and stirred at room temperature for 3 days. The reaction solution was concentrated under reduced pressure until it was about half volume. The produced precipitate was collected by suction filtration and washed with 1,2-dimethoxyethane and ether to obtain a crystalline powder. The obtained crystalline powder was added to a saturated aqueous sodium hydrogen carbonate solution (1200 ml) and stirred vigorously until the foaming subsided. The precipitate was collected by filtration under reduced pressure, and washed with a saturated aqueous sodium bicarbonate solution and water. The obtained solid was dried under reduced pressure to obtain the title compound (94. Og, 74%).
NMR(CDC1 ) δ : 7. 06 (1H, d, J = 9. 3Hz) , 7. 79 (1H, d, J= l . 2Hz) , 7. 9  NMR (CDC1) δ: 7.06 (1H, d, J = 9.3Hz), 7.79 (1H, d, J = l.2Hz), 7.9
3  Three
2 (1H, d, J = 9. 3Hz) , 7. 95 (1H, br s) .  2 (1H, d, J = 9.3Hz), 7.95 (1H, br s).
(工程 2) 3—ブロモー 6—クロロイミダゾ [1 , 2— b]ピリダジン  (Step 2) 3-Bromo-6-chloroimidazo [1, 2-b] pyridazine
[0200] [化 44] [0200] [Chemical 44]
Figure imgf000063_0001
Figure imgf000063_0001
[0201] 6—クロロイミダゾ [1 , 2— b]ピリダジン（74. Og, 482mmol)を氷酢酸（500ml)に 溶解し、この溶液に室温、攪拌下に臭素（32ml, 625mmol)を 2時間で滴下した。 滴下終了後、反応混合液を室温で 14時間攪拌した。生じた沈殿物を吸引ろ取、氷 酢酸及びエーテルで洗浄して結晶性粉末を得た。さらに、ろ液を減圧濃縮し、得られ た沈殿物を吸引ろ取し、これを氷酢酸及びエーテルで洗浄して結晶性粉末を得た。 得られた結晶性粉末を、ジクロロメタン（1000ml)に溶解し、これを 1N水酸化ナトリウ ム水溶液（1000ml)で洗浄した。ジクロロメタン層を分離し、無水硫酸ナトリウムで乾 燥した。不溶物をろ過後、ろ液を減圧濃縮した。得られた固形物をへキサン/酢酸ェ チル混合液（10 : 1)に懸濁し、減圧下にろ取して標記化合物（102. 8g, 92%)を得 た。 [0201] 6-Chloroimidazo [1, 2-b] pyridazine (74. Og, 482 mmol) was dissolved in glacial acetic acid (500 ml), and bromine (32 ml, 625 mmol) was added to this solution with stirring at room temperature over 2 hours. It was dripped. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 14 hours. The resulting precipitate was collected by suction filtration and washed with glacial acetic acid and ether to obtain a crystalline powder. Further, the filtrate was concentrated under reduced pressure, and the resulting precipitate was collected by suction filtration, and washed with glacial acetic acid and ether to obtain a crystalline powder. The obtained crystalline powder was dissolved in dichloromethane (1000 ml) and washed with 1N aqueous sodium hydroxide solution (1000 ml). The dichloromethane layer was separated and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was suspended in a hexane / ethyl acetate mixture (10: 1) and collected by filtration under reduced pressure to obtain the title compound (102.8 g, 92%).
NMR(CDC1 ) δ : 7. 12 (1H, d, J = 8. 8Hz) , 7. 79 (1H, s) , 7. 90 (1H, d, J =  NMR (CDC1) δ: 7.12 (1H, d, J = 8.8Hz), 7. 79 (1H, s), 7. 90 (1H, d, J =
3  Three
8. 8Hz) . [実施例 1] 4-[6-[(3, 4ージクロ口ベンジル)ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル] N— [2 （ジメチルァミノ）ェチル]ベンズアミド 塩酸塩 8.8Hz) [Example 1] 4- [6-[(3,4-Dichlorodiethyl) amino] imidazo [1,2-b] pyridazine 3-yl] N— [2 (dimethylamino) ethyl] benzamide hydrochloride
(工程 1) 3—ブロモ—6— [(3, 4—ジクロロベンジル）ァミノ]イミダゾ [1, 2— b]ピリ  (Step 1) 3-Bromo-6-[(3,4-dichlorobenzyl) amino] imidazo [1,2-b] pyri
[0202] [化 45] [0202] [Chemical 45]
Figure imgf000064_0001
Figure imgf000064_0001
[0203] [参考例 1]に記載の 3 ブロモー 6 クロロイミダゾ [1, 2— b]ピリダジン（1.20g, 5. 16mmol)、 3, 4 ジクロロペンジノレアミン（2.76ml, 20.7mmol)及び DMSO ( 2.5ml)の混合物を、 130°Cで 3時間攪拌した。反応混合液を室温に冷却後、 3, 4 —ジクロ口ベンジルァミン（2· 3ml, 17.2mmol)を追加し、 150°Cで 13時間攪拌し た。反応液を室温に冷却後、酢酸ェチルで希釈し、 2%クェン酸水溶液及び飽和食 塩水で洗浄した。酢酸ェチル層を分離し、さらに水層を酢酸ェチルで抽出した。あわ せた酢酸ェチル層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた固形物を エーテルで洗浄して標記化合物（1.18g, 61%)を得た。 [0203] 3 Bromo-6 chloroimidazo [1, 2-b] pyridazine (1.20 g, 5. 16 mmol), 3, 4 dichloropentinoreamine (2.76 ml, 20.7 mmol) and DMSO ( 2.5 ml) of the mixture was stirred at 130 ° C. for 3 hours. The reaction mixture was cooled to room temperature, 3,4-dichlorodibenzylamine (2.3 ml, 17.2 mmol) was added, and the mixture was stirred at 150 ° C. for 13 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with 2% aqueous citrate solution and saturated brine. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. The dried ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained solid was washed with ether to obtain the title compound (1.18 g, 61%).
NMR(DMSO-d ) δ :4.46 (2Η, d, J = 5.9Hz) , 6.77(1H, d, J = 9.7Hz) ,  NMR (DMSO-d) δ: 4.46 (2Η, d, J = 5.9Hz), 6.77 (1H, d, J = 9.7Hz),
6  6
7.44(1H, dd, J = 8.3, 2.1Hz), 7.53(1H, s) , 7.60(1H, d, J = 8.3Hz) , 7.73(1H, d, J = 2.1Hz), 7.75(1H, d, J = 9.7Hz) , 7.79(1H, br t, J = 5. 9Hz).  7.44 (1H, dd, J = 8.3, 2.1Hz), 7.53 (1H, s), 7.60 (1H, d, J = 8.3Hz), 7.73 (1H, d, J = 2.1Hz), 7.75 (1H, d , J = 9.7Hz), 7.79 (1H, br t, J = 5.9Hz).
MS (LC) m/z： 371 (M+ + H) . MS (LC) m / z: 371 (M + + H).
(工程 2) 4-[6-[(3, 4ージクロ口ベンジル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3—ィル]安息香酸 ェチル エステル  (Step 2) 4- [6-[(3,4-Dichlorodiethyl) amino] imidazo [1,2-b] pyridazine 3-yl] benzoic acid ethyl ester
[0204] [化 46] [0204] [Chem 46]
Figure imgf000065_0001
Figure imgf000065_0001
3 ブロモー 6—[(3, 4 ジクロ口ベンジル）ァミノ]イミダゾ [1, 2— b]ピリダジン（5 OOmg, 1.34mmol)、 4 エトキシカノレポニノレフェニノレボロン酸（340mg, 1.75m mol)、 [PdCl (dppf)]/ジクロロメタン錯体（1:1) (llOmg, 0.135mmol)、 dppf ( 3 Bromo 6-[(3, 4 Dicloccylbenzyl) amino] imidazo [1, 2-b] pyridazine (5 OOmg, 1.34mmol), 4 Ethoxycanoleponino levenoreboronic acid (340mg, 1.75mmol), [ PdCl (dppf)] / dichloromethane complex (1: 1) (llOmg, 0.135mmol), dppf (
2  2
75mg, 0. 135mmol)、リン酸三カリウム（水和物）（1.80g)及び 1, 4 ジォキサン（ 40ml)の混合液を、窒素気流下、 90— 95°Cで 18時間撹拌した。反応混合液を室温 に冷却後、 4 エトキシカルボユルフェニルボロン酸（180mg, 0.929mmol)、 [Pd CI (dppf)]/ジクロロメタン錯体（1:1) (llOmg, 0.135mmol)及び dppf (75mg 75 mg, 0.135 mmol), tripotassium phosphate (hydrate) (1.80 g) and 1,4 dioxane (40 ml) were stirred at 90-95 ° C. for 18 hours under a nitrogen stream. After cooling the reaction mixture to room temperature, 4 ethoxycarbophenyl phenylboronic acid (180 mg, 0.929 mmol), [Pd CI (dppf)] / dichloromethane complex (1: 1) (llOmg, 0.135 mmol) and dppf (75 mg
2 2
, 0.135mmol)を追加し、窒素気流下、 90— 95°Cで 4時間撹拌した。反応液を室 温に冷却後、酢酸ェチルを加え、不溶物をセライトを用いたろ過で除去した。ろ液を 減圧濃縮し、得られた残留物をフラッシュシリカゲルクロマトグラフィーに付した。ジク ロロメタン:メタノール = 20: 1溶出部より得た分画を減圧濃縮した。得られた固形物を へキサン/酢酸ェチル混合液（2： 1)で洗浄して標記化合物（288mg, 49%)を得た  , 0.135 mmol), and the mixture was stirred at 90 to 95 ° C for 4 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, ethyl acetate was added, and insolubles were removed by filtration using celite. The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from the eluate with dichloromethane: methanol = 20: 1 was concentrated under reduced pressure. The resulting solid was washed with a hexane / ethyl acetate mixture (2: 1) to give the title compound (288 mg, 49%).
NMR(CDC1 ) δ :1.43 (3Η, t, J = 7.2Hz) , 4.41 (2H, q, J=7.2Hz) , 4.57 NMR (CDC1) δ: 1.43 (3Η, t, J = 7.2Hz), 4.41 (2H, q, J = 7.2Hz), 4.57
3  Three
(2H, d, J=5.6Hz), 6.56(1H, d, J = 9.3Hz) , 7.24— 7.28(1H, m) , 7.4 4(1H, d, J = 8.3Hz), 7.52(1H, d, J = 2. OHz) , 7.75(1H, d, J = 9.3Hz) , 7.89(1H, br s) , 7.98 (2H, d, J = 8.3Hz) , 8.05— 8.09(1H, m) , 8.07( 2H, d, J=8.3Hz).  (2H, d, J = 5.6Hz), 6.56 (1H, d, J = 9.3Hz), 7.24- 7.28 (1H, m), 7.4 4 (1H, d, J = 8.3Hz), 7.52 (1H, d , J = 2. OHz), 7.75 (1H, d, J = 9.3Hz), 7.89 (1H, br s), 7.98 (2H, d, J = 8.3Hz), 8.05— 8.09 (1H, m), 8.07 (2H, d, J = 8.3Hz).
MS (LC) m/z： 441 (M+ + H) . MS (LC) m / z: 441 (M + + H).
(工程 3) 4-[6-[(3, 4ージクロ口ベンジル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3—ィル]安息香酸 [0206] [化 47] (Step 3) 4- [6-[(3,4-Dichlorodiethyl) amino] imidazo [1,2-b] pyridazine 3-yl] benzoic acid [0206] [Chemical 47]
Figure imgf000066_0001
Figure imgf000066_0001
[0207] 4-[6-[(3, 4ージクロ口ベンジル）ァミノ]イミダゾ [1, 2 b]ピリダジンー3 ィル ]安息香酸 ェチル エステノレ（250mg, 0.566mmol)、メタノール（60ml)及び IN 水酸化ナトリウム水溶液（5.7ml)の混合液を、加熱還流下に 1時間攪拌下した。反 応液を室温に冷却後、減圧濃縮した。濃縮残渣に水及び 1N塩酸を加えて pH4とし た後、ジクロロメタン/メタノール混合液で抽出した。抽出液を飽和食塩水で洗浄し た後、無水硫酸マグネシウムで乾燥した。不溶物をろ過後、ろ液を減圧濃縮した。得 られた固形物をジクロロメタンで洗浄して標記化合物（83mg, 36%)を得た。 [0207] 4- [6-[(3,4-Dichlorodiethyl) amino] imidazo [1,2b] pyridazine-3yl] Ethylbenzoate Estenole (250mg, 0.566mmol), Methanol (60ml) and IN hydroxylation A mixture of aqueous sodium solution (5.7 ml) was stirred with heating under reflux for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water and 1N hydrochloric acid were added to the concentrated residue to adjust the pH to 4, followed by extraction with a dichloromethane / methanol mixture. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with dichloromethane to obtain the title compound (83 mg, 36%).
NMR(DMSO-d ) δ :4.52 (2Η, d, J = 5.6Hz) , 6.85(1H, d, J = 9.5Hz) ,  NMR (DMSO-d) δ: 4.52 (2Η, d, J = 5.6Hz), 6.85 (1H, d, J = 9.5Hz),
6  6
7.41(1H, dd, J = 8.3, 1.5Hz) , 7.60(1H, d, J = 8.3Hz) , 7.71(1H, d, J =1.5Hz), 7.81-7.87(1H, m) , 7.84(1H, d, J = 9.5Hz) , 7.95(2H, d, J = 8.3Hz), 8.01(1H, s), 8.09 (2H, d, J = 8.3Hz) , 12.86(1H, br s) . MS(LC)m/z:413(M+ + H). 7.41 (1H, dd, J = 8.3, 1.5Hz), 7.60 (1H, d, J = 8.3Hz), 7.71 (1H, d, J = 1.5Hz), 7.81-7.87 (1H, m), 7.84 (1H , d, J = 9.5Hz), 7.95 (2H, d, J = 8.3Hz), 8.01 (1H, s), 8.09 (2H, d, J = 8.3Hz), 12.86 (1H, br s) .MS ( LC) m / z: 413 ( M + + H).
(工程 4) 4-[6-[(3, 4ージクロ口ベンジル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル] N— [2 （ジメチルァミノ）ェチル]ベンズアミド 塩酸塩  (Step 4) 4- [6-[(3,4-Dichlorodiethyl) amino] imidazo [1,2-b] pyridazine 3-yl] N— [2 (dimethylamino) ethyl] benzamide hydrochloride
[0208] [化 48] [0208] [Chemical 48]
Figure imgf000066_0002
[0209] 4-[6-[(3, 4ージクロ口ベンジル）ァミノ]イミダゾ [1, 2 b]ピリダジンー3 ィル ]安息香酸（lOOmg, 0.242mmol)、N, N ジメチノレエチレンジァミン（0· 035ml , 0.319mmol)、 TEA(0.067ml, 0.481mmol)及び DMF (2. Oml)の混合液 に、 BOP(139mg, 0.314mmol)を加えた。反応液を室温で 5時間攪拌後、減圧 濃縮した。濃縮残渣に炭酸水素ナトリウム水溶液を加え、生じた沈殿物をろ取した。 得られた固形物を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、 移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。濃縮残渣を メタノールに溶解し、 1N塩酸 (エタノール溶液）を加えて減圧濃縮した。濃縮残渣に メタノールを加えて減圧濃縮を数回繰り返した。濃縮残渣にジクロロメタンを加え、固 形物をろ取後、へキサンを用いて洗浄した。得られた粉末状物質を減圧下、 80°Cで 乾燥して標記化合物（26mg, 19%)を得た。
Figure imgf000066_0002
[0209] 4- [6-[(3,4-Dichlorodibenzyl) amino] imidazo [1,2b] pyridazine-3yl] benzoic acid (lOOmg, 0.242mmol), N, N dimethylenoethylenediamine ( 0, 035 ml, 0.319 mmol), TEA (0.067 ml, 0.481 mmol) and DMF (2. Oml) were mixed with BOP (139 mg, 0.314 mmol). The reaction mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure. An aqueous sodium hydrogen carbonate solution was added to the concentrated residue, and the resulting precipitate was collected by filtration. The obtained solid was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. The concentrated residue was dissolved in methanol, 1N hydrochloric acid (ethanol solution) was added, and the mixture was concentrated under reduced pressure. Methanol was added to the concentrated residue and vacuum concentration was repeated several times. Dichloromethane was added to the concentrated residue, and the solid was collected by filtration and washed with hexane. The obtained powdery substance was dried under reduced pressure at 80 ° C. to obtain the title compound (26 mg, 19%).
NMR(DMSO-d ) δ :2.85(3H, s) , 2.86 (3H, s) , 3.29 (2H, q, J = 5.8H  NMR (DMSO-d) δ: 2.85 (3H, s), 2.86 (3H, s), 3.29 (2H, q, J = 5.8H
6  6
z), 3.66 (2H, q, J = 5.8Hz) , 4.53 (2H, d, J = 5.9Hz) , 7. 12(1H, br d, J = 10.3Hz), 7.43(1H, dd, J = 8.3, 2.0Hz) , 7.65(1H, d, J = 7.8Hz) , 7. 68(1H, d, J = 2.0Hz), 7.97— 8.03 (3H, m) , 8.11 (2H, d, J = 8.6 Hz), 8 .26(1H, br s) , 8.32(1H, br s), 8.89(1H, br s) .  z), 3.66 (2H, q, J = 5.8Hz), 4.53 (2H, d, J = 5.9Hz), 7.12 (1H, br d, J = 10.3Hz), 7.43 (1H, dd, J = 8.3, 2.0Hz), 7.65 (1H, d, J = 7.8Hz), 7.68 (1H, d, J = 2.0Hz), 7.97— 8.03 (3H, m), 8.11 (2H, d, J = 8.6 Hz), 8.26 (1H, br s), 8.32 (1H, br s), 8.89 (1H, br s).
IR(ATR)cm_1:3248, 3053, 2679, 1610, 1508, 1492, 1469, 1331, 1292IR (ATR) cm _1 : 3248, 3053, 2679, 1610, 1508, 1492, 1469, 1331, 1292
, 1028, 852, 831, 771. , 1028, 852, 831, 771.
MS (LC) m/z： 482 (M+ + H) . MS (LC) m / z: 482 (M + + H).
Anal. Calcd for C H CI N O-l.75HCM.75H 0:C, 49.81;H, 5.09;  Anal.Calcd for C H CI N O-l.75HCM.75H 0: C, 49.81; H, 5.09;
24 24 2 6 2  24 24 2 6 2
CI, 22.97;N, 14.52. Found :C, 49.96;H, 5.00; CI, 22.87;N, 14.32. CI, 22.97; N, 14.52.Found: C, 49.96; H, 5.00; CI, 22.87; N, 14.32.
[実施例 2] 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン[Example 2] 4- [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine
3 ィル] N— (2 アミノエチル）ベンズアミド トリフルォロ酢酸塩 3yl] N— (2 aminoethyl) benzamide trifluoroacetate
(工程 1) 3—ブロモー 6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジ ン  (Step 1) 3-Bromo-6-[(cyclopropylmethyl) amino] imidazo [1, 2-b] pyridazine
[0210] [化 49] [0210] [Chemical 49]
Figure imgf000068_0001
Figure imgf000068_0001
[0211] [参考例 1]に記載の 3 ブロモー 6 クロロイミダゾ [1, 2— b]ピリダジン（18· 6g, 80. Ommol)及び（シクロプロピルメチル）ァミン（15· 3ml, 176mmol)の混合液を、 110°Cで 22時間撹拌した。反応液を室温に冷却後、クロ口ホルムを加えて希釈し、こ れを順次、飽和クェン酸水溶液、飽和食塩水、飽和炭酸水素ナトリウム水溶液及び 飽和食塩水で洗浄後、クロ口ホルム層を無水硫酸ナトリウムで乾燥した。不溶物をろ 過後、ろ液を減圧濃縮して標記化合物（20.2g, 94%)を得た。 [0211] Mixed solution of 3 bromo-6 chloroimidazo [1, 2-b] pyridazine (18.6 g, 80. Ommol) and (cyclopropylmethyl) amine (15.3 ml, 176 mmol) described in [Reference Example 1] Was stirred at 110 ° C. for 22 hours. The reaction solution is cooled to room temperature, diluted with black mouth form, and washed successively with a saturated aqueous citrate solution, a saturated saline solution, a saturated aqueous sodium bicarbonate solution and a saturated saline solution. Dried over sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (20.2 g, 94%).
NMR(CDC1 ) δ :0.29— 0.35(2H, m) , 0.55— 0.62(2H, m) , 1.10— 1.1  NMR (CDC1) δ: 0.29- 0.35 (2H, m), 0.55- 0.62 (2H, m), 1.10- 1.1
3  Three
8(1H, m), 3.28 (2H, dd, J = 7.11, 5.39Hz), 4.62(1H, br s) , 6.45(1H , d, J = 9.56Hz), 7.47(1H, s) , 7.58(1H, d, J = 9.56Hz) .  8 (1H, m), 3.28 (2H, dd, J = 7.11, 5.39Hz), 4.62 (1H, br s), 6.45 (1H, d, J = 9.56Hz), 7.47 (1H, s), 7.58 ( 1H, d, J = 9.56Hz).
MS (LC) m/z： 267(M+ + H) . MS (LC) m / z: 267 (M + + H).
(工程 2) 4— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル]安息香酸  (Step 2) 4- [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] benzoic acid
[0212] [化 50] [0212] [Chemical 50]
Figure imgf000068_0002
Figure imgf000068_0002
[0213] 3 ブロモー 6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン（2· 3 Og, 7.49mmol)、 4 （ジヒドロキシボリル）安息香酸（1.46g, 8.79mmol)、ジク ロロビス（トリフエニルホスフィン）パラジウム（II) (310mg, 0.442mmol)、 2M炭酸 カリウム水溶液（23ml)及び 1, 4 ジォキサン（35ml)の混合液を、窒素気流中、加 熱還流下に 14時間攪拌した。反応液を室温に冷却後、 1, 4ージォキサンを減圧留 去した。残留物に 2M炭酸カリウム水溶液を加え、混合物を酢酸ェチルで洗浄した。 水層に濃塩酸を加えて中和し、生じた沈殿物を吸引ろ過でろ取した。得られた結晶 性粉末を、 50°Cで減圧乾燥して標記化合物（2.53g, 95%)を得た。 [0213] 3 Bromo-6 [(cyclopropylmethyl) amino] imidazo [1, 2-b] pyridazine (2 3 Og, 7.49 mmol), 4 (dihydroxyboryl) benzoic acid (1.46 g, 8.79 mmol), Dichlorobis (Triphenylphosphine) palladium (II) (310mg, 0.442mmol), 2M carbonic acid A mixed solution of an aqueous potassium solution (23 ml) and 1,4 dioxane (35 ml) was stirred for 14 hours under heating and reflux in a nitrogen stream. After cooling the reaction solution to room temperature, 1,4-dioxane was distilled off under reduced pressure. To the residue was added 2M aqueous potassium carbonate solution and the mixture was washed with ethyl acetate. Concentrated hydrochloric acid was added to the aqueous layer for neutralization, and the resulting precipitate was collected by suction filtration. The obtained crystalline powder was dried under reduced pressure at 50 ° C. to obtain the title compound (2.53 g, 95%).
NMR(DMSO-d ) δ :0.28— 0.33 (2Η, m) , 0.49— 0.54 (2Η, m) , 1.13  NMR (DMSO-d) δ: 0.28— 0.33 (2Η, m), 0.49— 0.54 (2Η, m), 1.13
6  6
-1.21(1Η, m), 3.19(2Η, dd, J = 6.9, 5.4Hz) , 6.79(1Η, d, J = 9.7Hz ), 7.24(1Η, t, J = 5.3Hz), 7.78(1Η, d, J = 9.7Hz) , 7.99— 8.03 (3Η, m), 8.34 (2Η, d, J = 9.1Hz).  -1.21 (1Η, m), 3.19 (2Η, dd, J = 6.9, 5.4Hz), 6.79 (1Η, d, J = 9.7Hz), 7.24 (1Η, t, J = 5.3Hz), 7.78 (1Η, d, J = 9.7Hz), 7.99— 8.03 (3Η, m), 8.34 (2Η, d, J = 9.1Hz).
MS(LC)m/z:309.6(M+ + H). MS (LC) m / z: 309.6 (M + + H).
(工程 3) 4— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル] N— [2—（tert ブトキシカルボニルァミノ）ェチル]ベンズアミド [0214] [化 51]  (Step 3) 4- [6 -— [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] N— [2- (tert-butoxycarbonylamino) ethyl] benzamide [0214] 51]
Figure imgf000069_0001
Figure imgf000069_0001
[0215] 4 [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2 b]ピリダジンー3 ィル]安 息香酸（1.50g, 4.86mmol)及び DMF(lOOml)の混合液に、（2 アミノエチル） 力ルバミン酸 tert ブチノレ エステル（1.17g, 7.30mmol)及び 4— (4, 6 ジメ トキシ一 1, 3, 5 トリァジン一 2 ィル） 4 メチルモルホリニゥム クロリド（2.43g , 9.73mmol)を加え、室温で 21時間攪拌した。反応混合物をろ過し、ろ液を減圧 濃縮した。濃縮残渣をシリカゲルクロマトグラフィーに付し、クロ口ホルム:メタノール = 10:1溶出部より得た分画を集め、減圧濃縮して標記化合物（1.74g, 79%)を得た [0215] 4 [6 [(Cyclopropylmethyl) amino] imidazo [1, 2 b] pyridazine-3-yl] benzoic acid (1.50 g, 4.86 mmol) and DMF (lOOml) in a mixture of (2 amino Ethyl) Powerful rubamic acid tert butynole ester (1.17 g, 7.30 mmol) and 4— (4, 6 dimethoxy-1, 3, 5 triazine-2-yl) 4 methylmorpholinum chloride (2.43 g, 9.73 mmol) And stirred at room temperature for 21 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The concentrated residue was subjected to silica gel chromatography, and the fractions obtained from the eluate of black mouth form: methanol = 10: 1 were collected and concentrated under reduced pressure to obtain the title compound (1.74 g, 79%).
NMR(DMSO-d ) δ :0.25— 0.30 (2Η, m) , 0.48— 0.54 (2Η, m) , 1.12 -1.22(1H, m), 1.37(9H, s) , 3.12(2H, dd, J=ll.7, 5.9Hz) , 3.18(2 H, dd, J = 6.8, 5.4Hz), 3.31— 3.34 (2H, m) , 6.76(1H, d, J = 9.8Hz) , 6.90(1H, t, J = 5.9Hz), 7.20(1H, t, J = 5.2Hz) , 7.75(1H, d, J = 9.8H z), 7.91 (2H, d, J = 8.3Hz), 7.98(1H, s) , 8.29 (2H, d, J = 8.3Hz) , 8.4 5(1H, t, J = 5.1Hz). NMR (DMSO-d) δ: 0.25- 0.30 (2Η, m), 0.48— 0.54 (2Η, m), 1.12 -1.22 (1H, m), 1.37 (9H, s), 3.12 (2H, dd, J = ll.7, 5.9Hz), 3.18 (2 H, dd, J = 6.8, 5.4Hz), 3.31— 3.34 ( 2H, m), 6.76 (1H, d, J = 9.8Hz), 6.90 (1H, t, J = 5.9Hz), 7.20 (1H, t, J = 5.2Hz), 7.75 (1H, d, J = 9.8 H z), 7.91 (2H, d, J = 8.3Hz), 7.98 (1H, s), 8.29 (2H, d, J = 8.3Hz), 8.4 5 (1H, t, J = 5.1Hz).
MS (LC) m/z :451 (M+ + H) . MS (LC) m / z: 451 (M + + H).
(工程 4) 4— [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル] N— (2—アミノエチル）ベンズアミド トリフルォロ酢酸塩  (Step 4) 4— [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] N— (2-aminoethyl) benzamide trifluoroacetate
[化 52]  [Chemical 52]
Figure imgf000070_0001
Figure imgf000070_0001
[0217] 4-[6-[ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィル] N— [2— (tert ブトキシカルボニルァミノ）ェチル]ベンズアミド（1· 74g, 3.86mm ol)、ジクロロメタン（50ml)及びトリフルォロ酢酸（20ml)の混合液を、室温で 90分間 撹拌した。反応液を減圧濃縮して標記化合物（3.34g, 79%)を得た。 [0217] 4- [6-[(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3-yl] N- [2- (tert-butoxycarbonylamino) ethyl] benzamide (1.774g, 3.86 mm ol), dichloromethane (50 ml) and trifluoroacetic acid (20 ml) were stirred at room temperature for 90 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound (3.34 g, 79%).
MS (LC) m/z： 351 (M+ + H) . MS (LC) m / z: 351 (M + + H).
[実施例 3] 4— [6 [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル] N— [2 （イソプロピルァミノ）ェチル]ベンズアミド ギ酸塩  [Example 3] 4— [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3yl] N— [2 (Isopropylamino) ethyl] benzamide formate
[0218] [化 53] [0218] [Chemical 53]
Figure imgf000070_0002
[0219] [実施例 2]に記載の 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリ ダジンー3 ィル]—N— (2 アミノエチル）ベンズアミド トリフルォロ酢酸塩（44。 8 mg, 96. 5〃11101)にアセトン（5. Q μ\, 96. 5〃 mol)、シァノ水素ィ匕ホウ素ナトリウム (6. lmg, 96. 5 mol)及びメタノール（lml)を加え 24時間撹拌した。反応混合液 にアセトン（5. 6^1, 96. 5 mol)を追加して 170分間撹拌した。次いで反応混合 液にシァノ水素化ホウ素ナトリウム（6. lmg, 96. 5 mol)を追加して 22時間撹拌し た。得られた反応混合物に酢酸（3滴）を加えて 21日間静置した。反応混合物にァセ トン（11· 2μ\, 193 mol)を追加して 18時間撹拌後、シァノ水素化ホウ素ナトリウ ム（12. 2mg, 193 mol)を追加し 3日間撹拌した。反応液を減圧濃縮し、得られた 残渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァ セトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮して標記化合物（16. 7mg) を得た。
Figure imgf000070_0002
[0219] 4- [6-[(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -N- (2 aminoethyl) benzamide trifluoroacetate described in [Example 2] (44. 8 mg, 96.5-11101) with acetone (5. Q μ \, 96.5 mol), sodium cyanoborohydride (6. lmg, 96.5 mol) and methanol (lml). The mixture was stirred for 24 hours. Acetone (5.6 ^ 1, 96.5 mol) was added to the reaction mixture and stirred for 170 minutes. Next, sodium cyanoborohydride (6. lmg, 96.5 mol) was added to the reaction mixture, followed by stirring for 22 hours. Acetic acid (3 drops) was added to the resulting reaction mixture and allowed to stand for 21 days. After adding acetone (11.2 μ \, 193 mol) to the reaction mixture and stirring for 18 hours, sodium cyanoborohydride (12.2 mg, 193 mol) was added and stirred for 3 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the desired fraction was concentrated under reduced pressure to give the title compound. (16.7 mg) was obtained.
MS (LC) m/z： 393 (M+ + H) . MS (LC) m / z: 393 (M + + H).
[実施例 4] 4 [6 [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル] N— [2 （ジメチルァミノ）ェチル]ベンズアミド 2塩酸塩  [Example 4] 4 [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3yl] N— [2 (dimethylamino) ethyl] benzamide dihydrochloride
[0220] [化 54] [0220] [Chemical 54]
Figure imgf000071_0001
Figure imgf000071_0001
[0221] [実施例 2]に記載の 4 [6 [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリ ダジン 3 ィル]安息香酸（0· 272g, 0. 882mmol)及び DMF(lOml)の溶液に 、 N, N ジメチノレエチレンジァミン（0. 116ml, 1. 06mmol)、 4一（4, 6 ジメトキ シー 1, 3, 5 トリアジンー 2 ィノレ） 4ーメチノレモノレホリュウム クロリド（0· 265g, 1. 06mmol)を加えて 70時間撹拌した。反応液を減圧濃縮し、得られた残渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリノレ /水/ギ酸)で精製し、 目的分画を減圧濃縮した。濃縮残渣に 1N塩酸 (エタノール 溶液）を加え、減圧濃縮して標記化合物（186mg, 45%)を得た。 [0221] 4 [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3-yl] benzoic acid (0 · 272 g, 0. 882 mmol) and DMF (described in Example 2) lOml) solution, N, N dimethylenoethylenediamine (0.116 ml, 1.06 mmol), 4 (4, 6 dimethoxy 1, 3, 5 triazine-2-inole) 4-methinoremonochlorium chloride (0 · 265 g, 1.06 mmol) was added and stirred for 70 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was fractionated. The product was purified by HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. 1N Hydrochloric acid (ethanol solution) was added to the concentrated residue, and the mixture was concentrated under reduced pressure to obtain the title compound (186 mg, 45%).
NMR(DMSO-d ) δ :0.25— 0.33 (2Η, m) , 0.50— 0.55(2Η, m) , 1.10 NMR (DMSO-d) δ: 0.25- 0.33 (2Η, m), 0.50- 0.55 (2Η, m), 1.10
6  6
-1.21(1Η, m), 2.82(7Η, d, J = 4.9Hz) , 3.17— 3.28 (2Η, m) , 3.28(2 Η, q, J = 5.8Hz), 3.66 (2Η, q, J = 5.8Hz) , 7.25(1Η, d, J = 9.8Hz) , 7.9 8(1Η, br s), 8.04(1Η, d, J = 9.8Hz) , 8.10(2Η, d, J = 8.5Hz) , 8.28(2 Η, d, J = 8.5Hz), 8.52(1Η, s) , 9.00(1Η, t, J = 5.5Hz) , 10.35(1Η, br s).  -1.21 (1Η, m), 2.82 (7Η, d, J = 4.9Hz), 3.17— 3.28 (2Η, m), 3.28 (2 Η, q, J = 5.8Hz), 3.66 (2Η, q, J = 5.8Hz), 7.25 (1Η, d, J = 9.8Hz), 7.9 8 (1Η, br s), 8.04 (1Η, d, J = 9.8Hz), 8.10 (2Η, d, J = 8.5Hz), 8.28 (2 Η, d, J = 8.5 Hz), 8.52 (1 Η, s), 9.00 (1 Η, t, J = 5.5 Hz), 10.35 (1 Η, br s).
Anal. Calcd for C H N 0-2HC1-H 0:C, 53.73;H, 6.44; CI, 15. 11;  Anal.Calcd for C H N 0-2HC1-H 0: C, 53.73; H, 6.44; CI, 15. 11;
21 26 6 2  21 26 6 2
N, 17.90. Found :C, 53.47;H, 6.46; CI, 15.06;N, 17.81.  N, 17.90.Found: C, 53.47; H, 6.46; CI, 15.06; N, 17.81.
MS (LC) m/z： 379 (M+ + H) . MS (LC) m / z: 379 (M + + H).
[実施例 5] 4— [6 [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル] N— [2 （ジメチルァミノ）ェチル] N メチルベンズアミド 2塩酸塩 [化 55]  [Example 5] 4- [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3-yl] N- [2 (dimethylamino) ethyl] N-methylbenzamide dihydrochloride
Figure imgf000072_0001
Figure imgf000072_0001
[実施例 2]に記載の 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリ ダジンー3 ィノレ]安息香酸（150mg, 0.486mmol)、N, N, N，ートリメチルェチレ ンジァミン（0.100ml, 0.769mmol)及び DMF(7.0ml)の混合液に、 4— (4, 6 —ジメトキシ一 1, 3, 5—トリァジン一 2—ィル） 4—メチルモルホリニゥム クロリド（1 95mg, 0.779mmol)を加え、室温で 14時間攪拌した。反応混合物を減圧濃縮し、 濃縮残渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相 ：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。残渣に 1N塩酸 (ェ タノール溶液）を加え、減圧濃縮した。得られた固形物を酢酸ェチルで洗浄後、 90 °Cで 3日間減圧乾燥して標記化合物（157mg, 68%)を得た。 4- [6-[(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-inole] benzoic acid (150 mg, 0.486 mmol), N, N, N, 4- (4, 6-dimethoxy-1,3,5-triazine-2-yl) 4-methylmorpholinium in a mixture of trimethylethylenediamine (0.100 ml, 0.769 mmol) and DMF (7.0 ml) Methylene chloride (1 95 mg, 0.779 mmol) was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was subjected to preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase : Acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. 1N hydrochloric acid (ethanol solution) was added to the residue, and the mixture was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate and dried under reduced pressure at 90 ° C. for 3 days to obtain the title compound (157 mg, 68%).
NMR(DMSO-d ) δ :0.26— 0.31 (2Η, m) , 0.49— 0.55(2Η, m) , 1.11 NMR (DMSO-d) δ: 0.26— 0.31 (2 Η, m), 0.49— 0.55 (2 Η, m), 1.11
6  6
-1. 19(1Η, m), 2.88 (6Η, br s) , 3.00 (3Η, s) , 3.18(2Η, t, J = 5.5Hz) , 3.34-3.40 (2Η, m) , 3.84 (2Η, br s) , 7.14(1Η, d, J = 9.8Hz) , 7.67 (2Η, d, J=7.4Hz), 7.76(1Η, br s) , 7.98(1Η, d, J = 9.8Hz) , 8.24 (2Η , d, J=8.6Hz), 8.36(1Η, s).  -1.19 (1Η, m), 2.88 (6Η, br s), 3.00 (3Η, s), 3.18 (2Η, t, J = 5.5Hz), 3.34-3.40 (2Η, m), 3.84 (2Η, br s), 7.14 (1Η, d, J = 9.8Hz), 7.67 (2Η, d, J = 7.4Hz), 7.76 (1Η, br s), 7.98 (1Η, d, J = 9.8Hz), 8.24 ( 2Η, d, J = 8.6Hz), 8.36 (1Η, s).
IR(ATR)cm_1:3253, 3049, 2578, 2474, 1624, 1537, 1502, 1466, 1406 , 1348, 1281, 1238, 1080, 1016, 831, 764, 667, 586, 476. IR (ATR) cm _1 : 3253, 3049, 2578, 2474, 1624, 1537, 1502, 1466, 1406, 1348, 1281, 1238, 1080, 1016, 831, 764, 667, 586, 476.
MS(LC)m/z:309.6(Μ+ + Η). MS (LC) m / z: 309.6 (Μ + + Η).
Anal. Calcd for C Η Ν O-2HC1-0.75H 0:C, 55.17;H, 6.63;C1, 14  Anal.Calcd for C Η Ν O-2HC1-0.75H 0: C, 55.17; H, 6.63; C1, 14
22 28 6 2  22 28 6 2
.80;N, 17.55. Found :C, 55.37;H, 6.51;C1, 15.06;N, 17.45.  .80; N, 17.55.Found: C, 55.37; H, 6.51; C1, 15.06; N, 17.45.
[実施例 6] (±)—4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダ ジン— 3 ィル] N— [(1R, 2R) -2- (ジメチルァミノ）シクロへキシル]ベンズアミ ド 2塩酸塩  [Example 6] (±) —4— [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3 yl] N — [(1R, 2R) -2- (dimethylamino) ) Cyclohexyl] benzamide dihydrochloride
(工程 1) (±)— [(lR, 2R)—2—アミノシクロへキシル]力ルバミン酸 tert ブチ ノレ エステノレ  (Step 1) (±) — [(lR, 2R) —2-Aminocyclohexyl] power rubamic acid tert butynore Estenole
[化 56] [Chemical 56]
Figure imgf000073_0001
Figure imgf000073_0001
(土）一トランス 1, 2 シクロへキサンジァミン（5· 00g, 43.8mmol)をジクロロメ タン（80ml)に溶解し、氷冷下で 2—（tert ブトキシカルボニルォキシィミノ） 2— フエ二ルァセトニトリル（10.78g, 43.79mmol)を加え室温でー晚攪拌した。反応 液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィーに付し、ジクロロメタン:メ タノール =25: ;L溶出部より得た分画を減圧濃縮して標記化合物（5.94g, 74%)を 得た。 (Sat) 1-trans 1,2 Cyclohexanediamine (5.00 g, 43.8 mmol) was dissolved in dichloromethane (80 ml), and 2- (tert-butoxycarbonyloxyimino) 2-phenylacetonitrile ( 10.78 g, 43.79 mmol) was added and stirred at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, dichloromethane: methanol = 25:; title compound fractions obtained from L eluate was concentrated under reduced pressure (5 .94g, 74%) Obtained.
NMR(CDC1 ) δ :1.05— 1.34 (4H, m) , 1.45(9H, s)l.68— 1.75(2H, m  NMR (CDC1) δ: 1.05— 1.34 (4H, m), 1.45 (9H, s) l.68— 1.75 (2H, m
3  Three
)1.92-2.02 (2H, m) , 2.32(1H, dt, J=10.3, 3.9Hz) , 3.08— 3.20(1 ) 1.92-2.02 (2H, m), 2.32 (1H, dt, J = 10.3, 3.9Hz), 3.08-3.20 (1
H, m), 4.50(1H, br s) . H, m), 4.50 (1H, br s).
MS (FAB) m/z :215(M+ + H). MS (FAB) m / z: 215 (M + + H).
(工程 2) (±)— [(1R, 2R)— 2—（ジメチルァミノ）シクロへキシル]力ルバミン酸 t ert—プ'チノレ エステノレ  (Step 2) (±) — [(1R, 2R) — 2- (Dimethylamino) cyclohexyl] rubamic acid tert-tinole Estenole
[0226] [化 57]  [0226] [Chemical 57]
Figure imgf000074_0001
Figure imgf000074_0001
[0227] (±)— [(lR, 2R)—2—アミノシクロへキシル]力ルバミン酸 tert—ブチル エス テノレ（300mg, 1.40mmol)をメタノール（14ml)に溶解し、 36%ホルムアルデヒド 水溶液（1. 17ml, 14. Ommol)及びシァノ水素化ホウ素ナトリウム（264mg、 4.20 mmol)を加えて室温で 24時間攪拌した。反応混合物を減圧濃縮し、残渣をシリカゲ ルカラムクロマトグラフィーに付し、ジクロロメタン:メタノール = 9:1溶出部より得た分 画を減圧濃縮して標記化合物（250mg, 74%)を得た。 [0227] (±) — [(lR, 2R) -2-Aminocyclohexyl] strength tert-Butyl esterol (300 mg, 1.40 mmol) is dissolved in methanol (14 ml), and 36% aqueous formaldehyde solution (1 17 ml, 14. Ommol) and sodium cyanoborohydride (264mg, 4.20mmol) were added and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with dichloromethane: methanol = 9: 1 was concentrated under reduced pressure to obtain the title compound (250 mg, 74%).
NMR(CDC1 ) δ :1.14— 1.34 (4Η, m) , 1.46 (9Η, s) , 1.70— 1.92 (3Η,  NMR (CDC1) δ: 1.14— 1.34 (4Η, m), 1.46 (9 (, s), 1.70— 1.92 (392,
3  Three
m), 2.29-2.36(1Η, m) , 2.42(6Η, s) , 2.48— 2.59(1Η, m) , 3.30— 3 .41(1Η, m), 5.25(1Η, d, J = 5.6Hz) .  m), 2.29-2.36 (1Η, m), 2.42 (6Η, s), 2.48— 2.59 (1Η, m), 3.30— 3.41 (1Η, m), 5.25 (1Η, d, J = 5.6Hz) .
(工程 3) (±)—4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジ ン一 3—ィル] -N-[(1R, 2R)-2- (ジメチルァミノ）シクロへキシル]ベンズアミド 2塩酸塩  (Step 3) (±) —4— [6— [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -N-[(1R, 2R) -2- ( Dimethylamino) cyclohexyl] benzamide dihydrochloride
[0228] [化 58] [0228] [Chemical 58]
Figure imgf000075_0001
(±)— [(1R, 2R)— 2—（ジメチルァミノ）シクロへキシル]力ルバミン酸 tert ブ チル エステノレ（125mg, 0.52mmol)及び 4N塩酸（1, 4 ジォキサン溶液）（10m 1)の混合液を 12時間攪拌した。反応混合物を減圧濃縮し、得られた残渣、 [実施例 2 ]に記載の 4 -[6-[ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2-b]ピリダジン 3 ィル]安息香酸（159mg, 0.52mmol)及び DMF(7.0ml)の混合液に、 EDC (1 19mg, 0.62mmol)、 HOBt(16mg, 0. lOmmol)及び TEA(0.144ml, 1.03 mmol)を加えて室温でー晚攪拌した。反応混合液に水及び飽和炭酸水素ナトリウム 水溶液を加え、酢酸ェチルで抽出した。抽出液を、無水硫酸ナトリウムで乾燥、ろ過 後、ろ液を減圧濃縮した。濃縮残渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸)で精製した。 目的分画に炭酸 水素ナトリウムを加えて塩基性とし、ジクロロメタン/メタノール混合液で抽出した。抽 出液を無水硫酸ナトリウムで乾燥、減圧濃縮した。残渣にジクロロメタン/へキサン混 合液を加え、固形物をろ過して標記化合物（67mg, 30%)を得た。
Figure imgf000075_0001
(±) — [(1R, 2R) — 2- (Dimethylamino) cyclohexyl] -powered rubamate tert-butyl estenole (125 mg, 0.52 mmol) and 4N hydrochloric acid (1,4 dioxane solution) (10 ml) Was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue, 4- [6-[(cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3yl] benzoic acid (159 mg, described in Example 2). , 0.52 mmol) and DMF (7.0 ml) were added EDC (119 mg, 0.62 mmol), HOBt (16 mg, 0.1 mmol) and TEA (0.144 ml, 1.03 mmol) and stirred at room temperature. . Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi— RP-5, mobile phase: acetonitrile / water / formic acid). The target fraction was made basic by adding sodium hydrogen carbonate, and extracted with a dichloromethane / methanol mixture. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Dichloromethane / hexane mixture was added to the residue, and the solid was filtered to obtain the title compound (67 mg, 30%).
NMR(DMSO-d ) δ :0.30 (2Η, q, J = 4.8Hz) , 0.52 (2H, dd, J=12.7, 5 NMR (DMSO-d) δ: 0.30 (2Η, q, J = 4.8Hz), 0.52 (2H, dd, J = 12.7, 5
6  6
. 1Hz), 1.18-1.38 (4H, m) , 1.66(1H, d, J=10.5Hz) , 1.79(1H, d, J = 14.2Hz), 1.92(1H, d, J=ll.3Hz) , 2.55(1H, d, J = 9.8Hz) , 3.20(2 H, t, J = 6.0Hz), 3.30 (2H, s) , 3.32(6H, s) , 3.83— 3.93(1H, m) , 6.7 8(1H, d, J = 9.8Hz), 7.21(1H, t, J = 4.7Hz) , 7.77(1H, d, J = 9.8Hz) , 7.94 (2H, t, J = 6.0Hz), 7.99(1H, d, J = 4.9Hz) , 8.05(1H, d, J = 8.1H z), 8.30 (2H, d, J = 8.1Hz).  1Hz), 1.18-1.38 (4H, m), 1.66 (1H, d, J = 10.5Hz), 1.79 (1H, d, J = 14.2Hz), 1.92 (1H, d, J = ll.3Hz), 2.55 (1H, d, J = 9.8Hz), 3.20 (2 H, t, J = 6.0Hz), 3.30 (2H, s), 3.32 (6H, s), 3.83- 3.93 (1H, m), 6.7 8 (1H, d, J = 9.8Hz), 7.21 (1H, t, J = 4.7Hz), 7.77 (1H, d, J = 9.8Hz), 7.94 (2H, t, J = 6.0Hz), 7.99 (1H , d, J = 4.9Hz), 8.05 (1H, d, J = 8.1H z), 8.30 (2H, d, J = 8.1Hz).
IR(ATR)cm_1:3262, 3060, 1629, 1542, 1492, 1328, 1294, 1174, 796. MS(FAB)m/z:433.2719(Calcd for C H N 0:433.2716). [実施例 7] [ (3R) -3- (ジメチルァミノ）ピロリジン— 1—ィル] =[4-[6-[ (シク 口プロピルメチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン— 3—ィル]フエニル] =ケトン 2ギ酸塩 IR (ATR) cm _1 : 3262, 3060, 1629, 1542, 1492, 1328, 1294, 1174, 796.MS (FAB) m / z: 433.2719 (Calcd for CHN 0: 433.2716). [Example 7] [(3R) -3- (dimethylamino) pyrrolidine-1-yl] = [4- [6-[(cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3 Il] phenyl] ketone diformate
[化 59] [Chemical 59]
Figure imgf000076_0001
Figure imgf000076_0001
[実施例 2]に記載の 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリ ダジンー3—ィル]安息香酸（150mg, 0.49mmol)、（3R)— 3—(ジメチルァミノ）ピ 口リジン（0· 12ml, 0.97mmol)及び DMF(5ml)の混合液に、 EDC(112mg, 0. 58mmol)、 HOBt(14.9mg, 0. lOmmol)及び TEA(0.14ml, 0.97mmol)を 加え、室温で 24時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液（20ml )と酢酸ェチル（10ml)を加えて攪拌し、酢酸ェチルで抽出した。抽出液を無水硫酸 ナトリウムで乾燥後、減圧濃縮した。得られた残渣を分取 HPLC (カラム： NOMURA4- [6-[(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] benzoic acid (150 mg, 0.49 mmol), (3R) -3 described in [Example 2] — (Dimethylamino) pi-lysine (0 · 12 ml, 0.97 mmol) and DMF (5 ml) were mixed with EDC (112 mg, 0.58 mmol), HOBt (14.9 mg, 0.1 mmol) and TEA (0.14 ml, 0.97 mmol) was added and stirred at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate solution (20 ml) and ethyl acetate (10 ml) were added to the reaction mixture, and the mixture was stirred and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Preparative HPLC (column: NOMURA
Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し、標記 化合物（132mg, 58%)を得た。 Purification by Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid) gave the title compound (132 mg, 58%).
NMR(CD OD) δ :0.27-0.31 (2Η, m) , 0.56 (2Η, ddd, J = 8.3, 5.9, 4.  NMR (CD OD) δ: 0.27-0.31 (2Η, m), 0.56 (2Η, ddd, J = 8.3, 5.9, 4.
3  Three
2Hz), 1.14-1.24(1H, m) , 2.13— 2.53 (2H, br m) , 2.66— 3.03(6H , br m), 3.21 (2H, d, J = 7.1Hz), 3.64— 4. 11 (5H, m) , 6.76(1H, d, J = 10.0Hz), 7.62-7.67(1H, br m) , 7.63(1H, d, J = 9.6Hz) , 7.85(1 H, s), 8.25-8.29 (4H, m) .  2Hz), 1.14-1.24 (1H, m), 2.13— 2.53 (2H, br m), 2.66— 3.03 (6H, br m), 3.21 (2H, d, J = 7.1 Hz), 3.64— 4.11 ( 5H, m), 6.76 (1H, d, J = 10.0Hz), 7.62-7.67 (1H, br m), 7.63 (1H, d, J = 9.6Hz), 7.85 (1 H, s), 8.25-8.29 (4H, m).
IR(ATR)cm_1:3264, 1606, 1425, 1168, 813, 763. MS (LC) m/z： 405 (M+ + H) . IR (ATR) cm _1 : 3264, 1606, 1425, 1168, 813, 763. MS (LC) m / z: 405 (M + + H).
Anal. Calcd for C H N 0-2HCO H-0.25H 0:C, 59.93;H, 6.54;N,  Anal.Calcd for C H N 0-2HCO H-0.25H 0: C, 59.93; H, 6.54; N,
23 28 6 2 2  23 28 6 2 2
16.77. Found :C, 59.43;H, 6.87;N, 17.10.  16.77.Found: C, 59.43; H, 6.87; N, 17.10.
[実施例 8] (±)—4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダ ジン— 3 ィル] N— [(1R, 2R) -2- (ジメチルァミノ）シクロペンチル]ベンズアミ ド、  [Example 8] (±) -4— [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3 yl] N — [(1R, 2R) -2- (dimethylamino) ) Cyclopentyl] benzamide,
(工程 1) (±)— [(1R, 2R)— 2—（ジメチルァミノ）シクロペンチル]力ルバミン酸 t ert プ'チノレ エステノレ  (Step 1) (±) — [(1R, 2R) — 2- (Dimethylamino) cyclopentyl] strength rubamic acid t ert pino estole
[0232] [化 60]
Figure imgf000077_0001
[0232] [Chemical 60]
Figure imgf000077_0001
[0233] (±) [(lR, 2R)—2—アミノシクロペンチル]力ルバミン酸 tert ブチル エス テノレ（300mg, 1.50mmol)をメタノール（10ml)に溶解し、 36%ホルムアルデヒド 水溶液（47%) (1.25ml, 15. Ommol)及びシァノ水素化ホウ素ナトリウム（282mg , 4.49mmol)を加えた後、室温で 64時間攪拌した。反応混合物に無水硫酸ナトリ ゥムを加え、ろ過後、ろ液を減圧濃縮した。得られた残渣をフラッシュカラムクロマトグ ラフィ一に付し、ジクロロメタン:メタノール = 20: 1溶出部より得た分画を減圧濃縮し て標記化合物（250mg, 73%)を得た。 [0233] (±) [(lR, 2R) -2-Aminocyclopentyl] strength tert-butyl esterol rubamate (300 mg, 1.50 mmol) was dissolved in methanol (10 ml), and 36% aqueous formaldehyde solution (47%) (1.25 ml, 15. Ommol) and sodium cyanoborohydride (282mg, 4.49mmol) were added, followed by stirring at room temperature for 64 hours. To the reaction mixture was added anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash column chromatography, and the fraction obtained from the dichloromethane: methanol = 20: 1 eluate was concentrated under reduced pressure to give the title compound (250 mg, 73%).
NMR(CDC1 ) δ :1.44 (9Η, s) , 1.51— 1.73 (3Η, m) , 1.82— 1.91 (1Η,  NMR (CDC1) δ: 1.44 (9Η, s), 1.51— 1.73 (3Η, m), 1.82— 1.91 (1Η,
3  Three
m), 1.99-2.18(1H, m) , 2.40(6H, s) , 2.61— 2.89(2H, m) , 3.89(1H , br s), 4.74— 4.63(1H, br m) .  m), 1.99-2.18 (1H, m), 2.40 (6H, s), 2.61-2.89 (2H, m), 3.89 (1H, br s), 4.74-4.63 (1H, br m).
(工程 2) (±)—4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジ ン 3 ィル] -N-[(1R, 2R)-2- (ジメチルァミノ）シクロペンチル]ベンズアミド [0234] [化 61] (Step 2) (±) —4— [6— [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3 yl] -N-[(1R, 2R) -2- (dimethylamino) [Cyclopentyl] benzamide [0234] [Chemical Formula 61]
Figure imgf000078_0001
Figure imgf000078_0001
(±)— [(1R, 2R)— 2—（ジメチルァミノ）シクロペンチル]力ルバミン酸 tert—ブ チル エステノレ（125mg, 0.55mmol)及び 4N塩酸（1, 4—ジォキサン溶液）（10m 1)の混合液を、室温で 24時間攪拌した。反応混合物を減圧濃縮し、濃縮残渣にメタ ノール（5ml)を加えて溶媒を減圧濃縮した。得られた残渣を DMF (5ml)に溶解し、 [実施例 2]に記載の 4ー [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリ ダジン— 3—ィノレ]安息香酸（169mg, 0.55mmol)、 EDC(126mg, 0.66mmol) 、HOBt(16.8mg, 0.1 lmmol)及び TEA (0.15ml, 1.09mmol)をカロえて室温 で 24時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液（20ml)と酢酸ェ チル（10ml)を加えて攪拌後、酢酸ェチルで抽出した。抽出液を無水硫酸ナトリウム で乾燥後、減圧濃縮した。得られた残渣を分取 HPLC (カラム： NOMURA Devel osil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し、 目的分画を集 めた。 目的分画に炭酸水素ナトリウムを加えて塩基性とし、ジクロロメタン/メタノーノレ 混合液で抽出した。得られた抽出液を無水硫酸ナトリウムで乾燥後、減圧濃縮した。 残渣をジクロロメタン/へキサン混合液を加え、固形物をろ取して標記化合物（47m g, 20%)を得た。 (±) — [(1R, 2R) — 2- (Dimethylamino) cyclopentyl] force A mixture of tert-butyle esterol (125 mg, 0.55 mmol) and 4N hydrochloric acid (1,4-dioxane solution) (10 m 1) Was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, methanol (5 ml) was added to the concentrated residue, and the solvent was concentrated under reduced pressure. The obtained residue was dissolved in DMF (5 ml), and 4- [6 — [(cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-ynole] benzoic acid described in [Example 2] Acid (169 mg, 0.55 mmol), EDC (126 mg, 0.66 mmol), HOBt (16.8 mg, 0.1 lmmol) and TEA (0.15 ml, 1.09 mmol) were prepared and stirred at room temperature for 24 hours. A saturated aqueous sodium hydrogen carbonate solution (20 ml) and ethyl acetate (10 ml) were added to the reaction mixture, and the mixture was stirred and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (column: NOMURA Development Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fractions were collected. The target fraction was made basic by adding sodium bicarbonate and extracted with a dichloromethane / methanolate mixture. The obtained extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the residue was added a dichloromethane / hexane mixture, and the solid was collected by filtration to obtain the title compound (47 mg, 20%).
NMR(DMSO-d ) δ :0.28— 0.32 (2Η, m) , 0.52 (2Η, ddd, J = 8.1, 5.9  NMR (DMSO-d) δ: 0.28— 0.32 (2Η, m), 0.52 (2Η, ddd, J = 8.1, 5.9
6  6
, 4.4Hz), 1.13-1.23(1H, m) , 1.46— 1.61 (3H, m) , 1.63— 1.73(1H , m), 1.75-1.84 (1H, m) , 1.89— 1.98 (1H, m) , 2.77 (1H, q, J = 7.6H z), 3.19(2H, dd, J = 6.9, 5.4Hz) , 3.32(6H, s) , 4.24— 4.31(1H, m) , 6.78(1H, d, J = 9.6Hz), 7.21(1H, t, J = 5.3Hz) , 7.77(1H, d, J = 9.8H z), 7.94 (2H, d, J = 8.8Hz) , 7.98(1H, s) , 8.30 (2H, d, J = 8.6Hz) , 8.3 9(1H, d, J = 8.6Hz). , 4.4Hz), 1.13-1.23 (1H, m), 1.46— 1.61 (3H, m), 1.63— 1.73 (1H, m), 1.75-1.84 (1H, m), 1.89— 1.98 (1H, m), 2.77 (1H, q, J = 7.6H z), 3.19 (2H, dd, J = 6.9, 5.4Hz), 3.32 (6H, s), 4.24— 4.31 (1H, m), 6.78 (1H, d, J = 9.6Hz), 7.21 (1H, t, J = 5.3Hz), 7.77 (1H, d, J = 9.8H z), 7.94 (2H, d, J = 8.8Hz), 7.98 (1H, s), 8.30 (2H, d, J = 8.6Hz), 8.3 9 (1H, d, J = 8.6Hz).
IR(ATR)cm_1:3259, 2948, 1625, 1490, 1328, 1313, 1292, 1172, 796. MS(FAB)m/z:419.2558(Calcd for C H N 0 : 419.2559) . IR (ATR) cm _1 : 3259, 2948, 1625, 1490, 1328, 1313, 1292, 1172, 796.MS (FAB) m / z: 419.2558 (Calcd for CHN 0: 419.2559).
24 31 6  24 31 6
Anal. Calcd for C H N O-O.25H 0:C, 68. 14;H, 7.27;N, 19.87. F  Anal.Calcd for C H N O-O.25H 0: C, 68. 14; H, 7.27; N, 19.87. F
24 30 6 2  24 30 6 2
ound:C, 67.87;H, 7.20;N, 19.92. ound: C, 67.87; H, 7.20; N, 19.92.
[実施例 9] [ (2R)— 2— [ [ (3R) - 3 フルォロピロリジン— 1—ィル]メチル]ピロリ ジン 1 ィル] =[4-[6-[ (シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダ ジン一 3—ィノレ]フエニル] =ケトン  [Example 9] [(2R) — 2— [[(3R)-3 fluoropyrrolidine — 1-yl] methyl] pyrrolidine 1 yl] = [4- [6- [(cyclopropylmethyl) Amino] imidazo [1, 2— b] pyridazine 1 3-inole] phenyl] = ketone
(工程 1) (2R)—2—[[(3R)—3 フルォロピ口リジン 1 ィル]メチル]ピロリジン —1—力ノレボン酸 tert ブチノレ エステノレ  (Step 1) (2R) —2 -— [[(3R) —3 Fluoro-lipine lysine 1-yl] methyl] pyrrolidine —1--Norebonic acid tert Butinole Estenole
[化 62]
Figure imgf000079_0001
[Chemical 62]
Figure imgf000079_0001
(R)— (― )— 3 フノレオ口ピロリジン 塩酸塩（125mg, 1. OOmmol)、 （2R)— 2 —ホルミルピロリジン一 1—カルボン酸 tert ブチノレ エステノレ（239mg, 1.20m mol)、トリァセトキシ水素化ホウ素ナトリウム（318mg, 1.50mmol)、酢酸（0.086 ml, 1.50mmol)、 TEA(0. 139ml, 1. OOmmol)及びジクロロメタン（5ml)の混合 液を、室温で 16時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え 、室温で 5分攪拌した後、クロ口ホルムで抽出した。抽出液を飽和食塩水で洗浄、無 水硫酸ナトリウム乾燥後、溶媒を減圧濃縮した。得られた残留物をシリカゲルカラムク 口マトグラフィ一に付し、クロ口ホルム：メタノール =50:1溶出部より得た分画を減圧 濃縮して標記化合物（304mg, 100%)を得た。 (R) — (—) — 3 Phenoreol pyrrolidine hydrochloride (125 mg, 1. OOmmol), (2R) — 2 —Formylpyrrolidine mono 1-carboxylic acid tert Butinole Estenole (239 mg, 1.20 mmol), Triacetoxyborohydride A mixture of sodium (318 mg, 1.50 mmol), acetic acid (0.086 ml, 1.50 mmol), TEA (0.139 ml, 1.OOmmol) and dichloromethane (5 ml) was stirred at room temperature for 16 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes, and then extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the fraction obtained from the elution with chloroform: methanol = 50: 1 was concentrated under reduced pressure to obtain the title compound (304 mg, 100%).
NMR(CDC1 ) δ :1.47(9H, s) , 1.75— 2. 18(6H, m) , 2.41— 3.06 (6H,  NMR (CDC1) δ: 1.47 (9H, s), 1.75— 2. 18 (6H, m), 2.41— 3.06 (6H,
3  Three
m), 3.32 (2H, s) , 3.77— 3.99(1H, m) , 5.06— 5.25(1H, m) . m), 3.32 (2H, s), 3.77-3.99 (1H, m), 5.06-5.25 (1H, m).
(工程 2) (2R)— 2— [[(3R)— 3 フルォロピロリジン一 1—ィル]メチル]ピロリジン 2塩酸塩 [0238] [化 63]
Figure imgf000080_0001
(Step 2) (2R) — 2— [[(3R) — 3 Fluoropyrrolidine 1-yl] methyl] pyrrolidine dihydrochloride [0238] [Chemical 63]
Figure imgf000080_0001
[0239] (2R)— 2— [ [ (3R) - 3 フノレオ口ピロリジン一 1 ィル]メチル]ピロリジン一 1 力 ノレボン酸 tert ブチノレ エステル（304mg, 1. OOmmol)、ジクロロメタン（10ml) 及びトリフルォロ酢酸（10ml)の混合液を、室温で 2時間攪拌した。反応混合物を減 圧濃縮した。濃縮残渣に 1N塩酸 (エタノール溶液）を加えて減圧濃縮する操作を 3 回繰り返し、標記化合物（288mg, 100%)を得た。 [0239] (2R) — 2— [[(3R)-3 Phenoreol Pyrrolidine monoyl] methyl] Pyrrolidine mono 1 force Norebonic acid tert Butinole ester (304 mg, 1. OOmmol), Dichloromethane (10 ml) and Trifluoroacetic acid (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The operation of adding 1N hydrochloric acid (ethanol solution) to the concentrated residue and concentrating under reduced pressure was repeated three times to obtain the title compound (288 mg, 100%).
NMR(DMSO-d ) δ :1.61-1.74(1H, m) , 1.81— 2.33(5H, m) , 3.22  NMR (DMSO-d) δ: 1.61-1.74 (1H, m), 1.81-2.33 (5H, m), 3.22
6  6
-3.91 (9H, m), 5.49(1H, d, J = 53. 19Hz), 9.58(1H, S).  -3.91 (9H, m), 5.49 (1H, d, J = 53.19Hz), 9.58 (1H, S).
(工程 3) [(2R)— 2— [[(3R)— 3—フルォロピロリジン— 1—ィル]メチル]ピロリジ ン 1 ィル] =[4-[6-[ (シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジ ン— 3—ィル]フエニル] =ケトン  (Step 3) [(2R) — 2— [[(3R) — 3-Fluoropyrrolidine-1-yl] methyl] pyrrolidine 1 yl] = [4- [6- [(cyclopropylmethyl) Amino] imidazo [1, 2— b] pyridazine— 3—yl] phenyl] = ketone
[0240] [化 64] [0240] [Chemical 64]
Figure imgf000080_0002
Figure imgf000080_0002
[0241] (21¾—2—[[(31¾—3—フルォロピロリジンー1ーィル]メチル]ピロリジン 2塩酸 塩（114mg, 0.395mmol)、 [実施例 2]に記載の 4 [6 [(シクロプロピルメチノレ) ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル]安息香酸（lOlmg, 0.329mmol)、 EDC(95mg, 0.49mmol)、 HOBt (44mg, 0.33mmol)、 TEA(0.138ml, 0. 998mmol)及び DMF(3ml)の混合液を、室温で 17時間攪拌した。反応混合物を 減圧濃縮後、濃縮残渣にクロ口ホルムを加えた。クロ口ホルム溶液を、飽和炭酸水素 ナトリウム水溶液及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。不溶物 をろ過後、ろ液を減圧濃縮した。濃縮残渣を分取 HPLC (カラム： NOMURA Deve losil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製した。 目的分画を 減圧濃縮し、得られた濃縮液に飽和炭酸水素ナトリウム水溶液を加え、液性をアル力 リ性とした後、クロ口ホルムで抽出した。クロ口ホルム層を飽和食塩水で洗浄、無水硫 酸ナトリウムで乾燥、ろ過後、ろ液を減圧濃縮した。濃縮残渣を少量の酢酸ェチルに 溶解し、これをへキサン中に超音波をかけながら滴下した。得られた沈殿物をろ取し て標記化合物（85mg, 54%)を得た。 [0241] (21¾-2-[[(31¾-3-Fluoropyrrolidine-1-yl] methyl] pyrrolidine dihydrochloride (114 mg, 0.395 mmol), 4 [6 [(cyclo Propylmethinole) amino] imidazo [1,2-b] pyridazine-3 yl] benzoic acid (lOlmg, 0.329 mmol), A mixture of EDC (95 mg, 0.49 mmol), HOBt (44 mg, 0.33 mmol), TEA (0.138 ml, 0.998 mmol) and DMF (3 ml) was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and black mouthform was added to the concentrated residue. The black mouth form solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid). The target fraction was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the resulting concentrated solution to make it liquid and then extracted with black mouth form. The black mouth form layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was dissolved in a small amount of ethyl acetate and added dropwise to hexane while applying ultrasonic waves. The resulting precipitate was collected by filtration to give the title compound (85 mg, 54%).
NMR(CDC1 ) δ :0.27— 0.35(2H, m) , 0.56— 0.63(2H, m) , 1.12— 1.2  NMR (CDC1) δ: 0.27- 0.35 (2H, m), 0.56- 0.63 (2H, m), 1.12- 1.2
3  Three
3(1H, m), 1.73-2.25(7H, m) , 2.53— 3.13(3H, m) , 3.21— 3.89(3H , m), 3.47-3.64 (2H, m) , 3.97— 4.20(1H, m) , 4.39— 4.54 (2H, m) , 5. 19(1H, d, J = 56.87Hz), 6.49(1H, d, J = 9.80Hz), 7.61 (2H, d, J = 8 .33Hz), 7.69(1H, d, J = 9.56Hz), 7.84(1H, s), 8.16(2H, d, J = 8.33 Hz).  3 (1H, m), 1.73-2.25 (7H, m), 2.53— 3.13 (3H, m), 3.21— 3.89 (3H, m), 3.47-3.64 (2H, m), 3.97— 4.20 (1H, m ), 4.39—4.54 (2H, m), 5.19 (1H, d, J = 56.87Hz), 6.49 (1H, d, J = 9.80Hz), 7.61 (2H, d, J = 8.33Hz), 7.69 (1H, d, J = 9.56Hz), 7.84 (1H, s), 8.16 (2H, d, J = 8.33 Hz).
IR(ATR)cm_1:3299, 2962, 2798, 1606, 1577, 1490, 1425, 1332, 1286 , 1168, 954, 833, 811, 765. IR (ATR) cm_1 : 3299, 2962, 2798, 1606, 1577, 1490, 1425, 1332, 1286, 1168, 954, 833, 811, 765.
MS (LC) m/z： 463 (M+ + H) . MS (LC) m / z: 463 (M + + H).
Anal. Calcd for C H FN O-0.5H 0:C, 66.22;H, 6.84;F, 4.03;N,  Anal.Calcd for C H FN O-0.5H 0: C, 66.22; H, 6.84; F, 4.03; N,
26 31 6 2  26 31 6 2
17.82. Found :C, 66.23;H, 7.06;F, 3.91;N, 17.31.  17.82.Found: C, 66.23; H, 7.06; F, 3.91; N, 17.31.
[実施例 10] 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル]—N— [2 （ジメチルァミノ）ェチル ] 2 メチルベンズアミド 2塩酸塩 (工程 1)4ーブロモー 2 メチル安息香酸 メチル エステル  [Example 10] 4— [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3yl] —N— [2 (dimethylamino) ethyl] 2 methylbenzamide dihydrochloride (Step 1) ) 4-Bromo-2-methylbenzoic acid methyl ester
[化 65]
Figure imgf000081_0001
[0243] 4ーブロモー 2 メチル安息香酸（890mg, 4. 14mmol)のメタノール（50ml)溶液 に、氷冷下で塩化チォニル（0. 40ml, 5. 48mmol)を滴下した。滴下終了後、反応 混合液を加熱還流下に 14時間攪拌した。反応液を室温に冷却後、減圧濃縮した。 濃縮残渣のエーテル溶液を、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗 浄後、無水硫酸マグネシウムで乾燥した。不溶物をろ過後、ろ液を減圧濃縮して標 記化合物（948mg, 100%)を得た。 [Chemical 65]
Figure imgf000081_0001
[0243] To a solution of 4-bromo-2-methylbenzoic acid (890 mg, 4.14 mmol) in methanol (50 ml) was added dropwise thionyl chloride (0.40 ml, 5.48 mmol) under ice cooling. After completion of the dropwise addition, the reaction mixture was stirred for 14 hours with heating under reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The ether solution of the concentrated residue was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (948 mg, 100%).
NMR(CDC1 ) δ : 2. 58 (3Η, s) , 3. 88 (3Η, s) , 7. 38 (1Η, dm, J = 8. 5Hz) ,  NMR (CDC1) δ: 2.58 (3 Η, s), 3. 88 (3 Η, s), 7. 38 (1 Η, dm, J = 8.5 Hz),
3  Three
7. 41 - 7. 43 (1H, m) , 7. 78 (1H, d, J = 8. 5Hz) .  7. 41-7. 43 (1H, m), 7. 78 (1H, d, J = 8.5 Hz).
(工程 2) 2—メチルー 4— (4, 4, 5, 5—テトラメチルー 1 , 3, 2—ジォキサボロラン 2—ィル)安息香酸 メチル エステル  (Step 2) 2-methyl-4- (4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolane 2-yl) benzoic acid methyl ester
[0244] [化 66]
Figure imgf000082_0001
[0244] [Chemical 66]
Figure imgf000082_0001
[0245] 4ーブロモー 2 メチル安息香酸 メチル エステノレ（940mg, 4. lOmmol)、ビス（ ピナコラート）ジボロン（1. 70g, 6. 69mmol)、酢酸パラジウム（II) (50mg, 0. 223 mmol)、酢酸カリウム（1. 30g, 13. 2mmol)及び DMF (20ml)の混合液を、窒素 気流下、 90°Cで 14時間撹拌した。反応液を室温に冷却後、酢酸パラジウム (II) (50 mg, 0. 223mmol)を追加し、さらに窒素気流下、 90°Cで 9時間撹拌した。反応液を 室温に冷却後、酢酸ェチルを加え、不溶物をセライトを用いたろ過で除去した。ろ液 を減圧濃縮し、得られた残留物をフラッシュシリカゲルクロマトグラフィーに付し、へキ サン:酢酸ェチル = 30： 1溶出部より得た分画を減圧濃縮して標記化合物（654mg, 58%)を得た。 [0245] Methyl estenole (940 mg, 4. lOmmol), bis (pinacolato) diboron (1.70 g, 6. 69 mmol), palladium (II) acetate (50 mg, 0.223 mmol), potassium acetate A mixture of (1.30 g, 13.2 mmol) and DMF (20 ml) was stirred at 90 ° C. for 14 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, palladium (II) acetate (50 mg, 0.223 mmol) was added, and the mixture was further stirred at 90 ° C. for 9 hr under a nitrogen stream. The reaction solution was cooled to room temperature, ethyl acetate was added, and insoluble matters were removed by filtration using celite. The filtrate was concentrated under reduced pressure, the obtained residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane: ethyl acetate = 30: 1 eluate was concentrated under reduced pressure to give the title compound (654 mg, 58% )
NMR(CDC1 ) δ : 1. 35 (12H, s) , 2. 60 (3H, s) , 3. 89 (3H, s) , 7. 66 (1H, d  NMR (CDC1) δ: 1.35 (12H, s), 2.60 (3H, s), 3. 89 (3H, s), 7.66 (1H, d
3  Three
, J = 7. 7Hz) , 7. 68 (1H, s) , 7. 88 (1H, d, J = 7. 7Hz) .  , J = 7.7Hz), 7.68 (1H, s), 7.88 (1H, d, J = 7.7Hz).
MS (LC) m/z： 277 (M+ + H) . MS (LC) m / z: 277 (M + + H).
(工程 3) 4— [6 [ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジンー3 ィル] 2—メチル安息香酸 メチル エステル (Step 3) 4— [6 [(Cyclopropylmethyl) amino] imidazo [1, 2—b] pyridazine-3 Yl] 2-methylbenzoic acid methyl ester
[化 67] [Chemical 67]
Figure imgf000083_0001
Figure imgf000083_0001
[実施例 2]に記載の 3 ブロモー 6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2 —b]ピリダジン（650mg, 2.36mmol)、 2 メチノレー 4 （4, 4, 5, 5 テトラメチノレ -1, 3, 2 ジォキサボロランー2 ィル）安息香酸 メチル エステノレ（650mg, 2. 43mmol)、 [PdCl (dppf) ]/ジクロロメタン錯体（1： 1) (235mg, 0.288mmol)、 3 Bromo-6 [(cyclopropylmethyl) amino] imidazo [1, 2 —b] pyridazine (650 mg, 2.36 mmol) described in [Example 2], 2 methylolene 4 (4, 4, 5, 5 tetramethylol-1, 3, 2 dioxaborolane-2yl) methyl estenole benzoate (650mg, 2.43mmol), [PdCl (dppf)] / dichloromethane complex (1: 1) (235mg, 0.288mmol),
2  2
dppf(165mg, 0.298mmol)、リン酸三カリウム（水和物）（3· 3g)及び 1, 4 ジォ キサン（50ml)の混合液を、窒素気流下、 90— 95°Cで 14時間撹拌した。反応液を 室温に冷却後、 3 ブロモ—6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピ リダジン（lOOmg, 0.374mmol)、 [PdCl (dppf) ]/ジクロロメタン錯体（1： 1) (23 A mixture of dppf (165mg, 0.298mmol), tripotassium phosphate (hydrate) (3.3g) and 1,4 dioxane (50ml) was stirred at 90-95 ° C for 14 hours under nitrogen flow did. After cooling the reaction solution to room temperature, 3 bromo-6-[(cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine (lOOmg, 0.374 mmol), [PdCl (dppf)] / dichloromethane complex (1: one two Three
2  2
5mg, 0.288mmol)及び dppf (165mg, 0.298mmol)を追カロし、窒素気流下、 9 0— 95°Cで 14時間撹拌した。反応液を室温に冷却後、反応混合物に酢酸ェチルを 加え、不溶物をセライトを用いたろ過で除去した。ろ液を減圧濃縮し、得られた残留 物をフラッシュシリカゲルクロマトグラフィーに付し、ジクロロメタン：メタノール = 40: 1 溶出部より得た分画を減圧濃縮した。得られた固形物をへキサン/酢酸ェチル混合 液（1： 1)で洗浄して標記化合物（361mg, 46%)を得た。  5 mg, 0.288 mmol) and dppf (165 mg, 0.298 mmol) were added and stirred at 90-95 ° C. for 14 hours under a nitrogen stream. After cooling the reaction solution to room temperature, ethyl acetate was added to the reaction mixture, and insoluble materials were removed by filtration using celite. The filtrate was concentrated under reduced pressure, the obtained residue was subjected to flash silica gel chromatography, and the fraction obtained from the eluate of dichloromethane: methanol = 40: 1 was concentrated under reduced pressure. The obtained solid was washed with a hexane / ethyl acetate mixture (1: 1) to obtain the title compound (361 mg, 46%).
NMR(CDC1 ) δ :0.29— 0.35(2H, m) , 0.57— 0.64 (2H, m) , 1.16— 1.2  NMR (CDC1) δ: 0.29— 0.35 (2H, m), 0.57— 0.64 (2H, m), 1.16— 1.2
3  Three
6(1H, m), 2.69(3H, s) , 3.28 (2H, dd, J = 7.1, 5.4Hz) , 3.92 (3H, s) , 4 .52-4.57(1H, m), 6.50(1H, d, J = 9.6Hz) , 7.69(1H, d, J = 9.6Hz) , 7.89(1H, s), 8.02-8.04 (2H, m) , 8.09(1H, s) .  6 (1H, m), 2.69 (3H, s), 3.28 (2H, dd, J = 7.1, 5.4Hz), 3.92 (3H, s), 4.52-4.57 (1H, m), 6.50 (1H, d, J = 9.6Hz), 7.69 (1H, d, J = 9.6Hz), 7.89 (1H, s), 8.02-8.04 (2H, m), 8.09 (1H, s).
MS (LC) m/z： 337 (M+ + H) . MS (LC) m / z: 337 (M + + H).
(工程 4) 4— [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル] 2—メチル安息香酸 [0248] [化 68] (Step 4) 4- [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] 2-methylbenzoic acid [0248] [Chemical 68]
Figure imgf000084_0001
Figure imgf000084_0001
[0249] 4 [6 [ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2-b]ピリダジン 3 ィル] 2 メチル安息香酸 メチル エステノレ（150mg, 0.446mmol)、メタノーノレ（15ml) 及び IN水酸化ナトリウム水溶液（1.5ml)の混合液を、加熱還流下に 5時間攪拌し た。反応液を室温に冷却し、 1N塩酸（1.5ml)を加えて減圧濃縮した。残留固形物 を、水及びエーテルで洗浄後、減圧乾燥して標記化合物（131mg, 91%)を得た。 [0249] 4 [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3yl] 2 Methyl benzoate Methyl estenole (150 mg, 0.446 mmol), methanol (15 ml) and IN sodium hydroxide aqueous solution (1.5 ml) of the mixture was stirred for 5 hours under heating to reflux. The reaction mixture was cooled to room temperature, 1N hydrochloric acid (1.5 ml) was added, and the mixture was concentrated under reduced pressure. The residual solid was washed with water and ether and then dried under reduced pressure to obtain the title compound (131 mg, 91%).
NMR(DMSO-d ) δ :0.26— 0.31 (2Η, m) , 0.48— 0.54 (2Η, m) , 1.17  NMR (DMSO-d) δ: 0.26— 0.31 (2Η, m), 0.48— 0.54 (2Η, m), 1.17
6  6
-1.27(1Η, m), 2.60 (3Η, s) , 3.19(2Η, dd, J = 6.9, 5.4Hz) , 6.77(1Η , d, J = 9.6Hz), 7.26(1Η, t, J = 5.4Hz) , 7.77(1Η, d, J = 9.6Hz) , 7.91( 1Η, d, J=8.3Hz), 8.00(1Η, s), 8.10(1Η, dd, J = 8.3, 1.3Hz) , 8.27— 8.29(1Η, m), 12.74(1Η, br s) .  -1.27 (1Η, m), 2.60 (3Η, s), 3.19 (2Η, dd, J = 6.9, 5.4Hz), 6.77 (1Η, d, J = 9.6Hz), 7.26 (1Η, t, J = 5.4 Hz), 7.77 (1Η, d, J = 9.6Hz), 7.91 (1Η, d, J = 8.3Hz), 8.00 (1Η, s), 8.10 (1Η, dd, J = 8.3, 1.3Hz), 8.27— 8.29 (1Η, m), 12.74 (1Η, br s).
MS (LC) m/z： 323 (M+ + H) . MS (LC) m / z: 323 (M + + H).
(工程 5) 4— [6— [ (シクロプロピルメチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン— 3— ィル] N— [2—（ジメチルァミノ）ェチル] 2—メチルベンズアミド 2塩酸塩  (Step 5) 4- [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] N- [2- (dimethylamino) ethyl] 2-methylbenzamide dihydrochloride
[0250] [化 69] [0250] [Chem 69]
Figure imgf000084_0002
[0251] 4 [6 ミノ]イミダゾ [ 1 , 2— b]ピリダジン一 3—ィル]
Figure imgf000084_0002
[0251] 4 [6 Mino] imidazo [1,2-b] Pyridazine 3-yl]
2 メチル安息香酸（llOmg, 0.341mmol)、N, N ジメチルエチレンジァミン（0 .056ml, 0.510mmol)及び DMF(5. Oml)の混合 ί夜に、 4— (4, 6 ジメトキシ一 1, 3, 5 トリアジンー 2 ィノレ） 4ーメチノレモノレホリュウム クロリド（130mg, 0.52 Ommol)を加え、室温で 3日間攪拌した。反応混合物を減圧濃縮した。濃縮残渣を 分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニト リル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。濃縮残渣に 1N塩酸 (エタノー ル溶液）を加え、減圧濃縮して標記化合物（134mg, 84%)を得た。 2 Mixing of methylbenzoic acid (llOmg, 0.341mmol), N, N dimethylethylenediamine (0.056ml, 0.510mmol) and DMF (5.Oml) 3,5 Triazine-2-inole) 4-Methinoremonorephorium chloride (130 mg, 0.52 Ommol) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. The concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. 1N Hydrochloric acid (ethanol solution) was added to the concentrated residue, and the mixture was concentrated under reduced pressure to obtain the title compound (134 mg, 84%).
NMR(DMSO-d ) δ :0.25— 0.33 (2Η, m) , 0.50— 0.57(2Η, m) , 1.14  NMR (DMSO-d) δ: 0.25- 0.33 (2Η, m), 0.50- 0.57 (2Η, m), 1.14
6  6
-1.26(1Η, m), 2.46 (3Η, s) , 2.83(3Η, s) , 2.84 (3Η, s) , 3.24— 3.30 (2Η, m), 3.40-3.80 (4Η, m) , 7.30(1Η, d, J = 9.8Hz) , 7.56(0.2Η, d , J = 7.8Ηζ), 7.67(0.8Η, d, J = 8.1Hz), 8.00— 8. 15(4Η, m) , 8.54(1 Η, s), 8.70(0.8Η, t, J = 5.5Hz) , 8.83(0.2Η, t, J = 5.6Hz) .  -1.26 (1Η, m), 2.46 (3Η, s), 2.83 (3Η, s), 2.84 (3 (, s), 3.24— 3.30 (2Η, m), 3.40-3.80 (4Η, m), 7.30 (1Η , d, J = 9.8Hz), 7.56 (0.2Η, d, J = 7.8Ηζ), 7.67 (0.8Η, d, J = 8.1Hz), 8.00—8.15 (4Η, m), 8.54 (1Η , s), 8.70 (0.8Η, t, J = 5.5Hz), 8.83 (0.2Η, t, J = 5.6Hz).
MS (LC) m/z： 393 (M+ + H) . MS (LC) m / z: 393 (M + + H).
[実施例 11] 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル]—N— [2 （ジメチルァミノ）ェチル ] 3 メチルベンズアミド 2塩酸塩 (工程 1)3 メチルー 4 （4, 4, 5, 5 テトラメチルー 1, 3, 2 ジォキサボロラン 2—ィル)安息香酸 メチル エステル  [Example 11] 4— [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3yl] —N— [2 (dimethylamino) ethyl] 3 methylbenzamide dihydrochloride (Step 1) ) 3 Methyl-4 (4, 4, 5, 5 Tetramethyl-1, 3, 2 Dioxaborolane 2-yl) benzoic acid methyl ester
[0252] [化 70]
Figure imgf000085_0001
[0252] [Chemical 70]
Figure imgf000085_0001
4 ブロモ 3 メチル安息香酸 メチル エステノレ（1.00g, 4.37mmol)、ビス（ ピナコラート）ジボロン（1.70g, 6.69mmol)、酢酸パラジウム（II) (50mg, 0.223 mmol)、酢酸カリウム（1.30g, 13.2mmol)及び DMF (20ml)の混合液を、窒素 気流下、 90°Cで 14時間撹拌した。反応液を室温に冷却後、酢酸ェチルを加え、不 溶物をセライトを用いたろ過で除去した。ろ液を減圧濃縮し、得られた残留物をフラッ シュシリカゲルクロマトグラフィーに付し、へキサン：酢酸ェチル = 30: 1溶出部より得 た分画を減圧濃縮して標記化合物（800mg, 66%)を得た。 4 Bromo 3 Methyl benzoate Methyl Estenole (1.00g, 4.37mmol), Bis (pinacolato) diboron (1.70g, 6.69mmol), Palladium (II) acetate (50mg, 0.223mmol), Potassium acetate (1.30g, 13.2mmol) And DMF (20 ml) was stirred at 90 ° C. for 14 hours under a nitrogen stream. The reaction solution was cooled to room temperature, ethyl acetate was added, and the insoluble material was removed by filtration using celite. The filtrate is concentrated under reduced pressure and the resulting residue is flushed. Silica gel chromatography was performed, and the fraction obtained from the hexane: ethyl acetate = 30: 1 eluate was concentrated under reduced pressure to obtain the title compound (800 mg, 66%).
NMR(CDC1 ) δ :1. 35(12H, s) , 2. 57(3H, s) , 3. 91 (3H, s) , 7. 80 (2H, s  NMR (CDC1) δ: 1.35 (12H, s), 2.57 (3H, s), 3.91 (3H, s), 7.80 (2H, s
3  Three
), 7. 82(1H, s).  ), 7.82 (1H, s).
MS (LC) m/z： 277 (M+ + H) . MS (LC) m / z: 277 (M + + H).
(工程 2) 4— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル] 3—メチル安息香酸 メチル エステル  (Step 2) 4— [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] 3-methylbenzoic acid methyl ester
[化 71] [Chemical 71]
Figure imgf000086_0001
Figure imgf000086_0001
[実施例 2]に記載の 3 ブロモー 6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2 —b]ピリダジン（800mg, 2. 90mmol)、 3 メチノレー 4 （4, 4, 5, 5 テトラメチノレ -1, 3, 2 ジォキサボロランー2 ィル）安息香酸 メチル エステノレ（800mg, 2. 99mmol)、 [PdCl (dppf) ]/ジクロロメタン錯体（1： 1) (285mg, 0. 349mmol)、 3 Bromo-6 [(cyclopropylmethyl) amino] imidazo [1, 2 —b] pyridazine (800 mg, 2.90 mmol), 3 Methylenole 4 (4, 4, 5, 5 tetramethinole -1 described in [Example 2] , 3, 2 Dioxaborolane-2-yl) methyl estenole benzoate (800 mg, 2. 99 mmol), [PdCl (dppf)] / dichloromethane complex (1: 1) (285 mg, 0.349 mmol),
2  2
dppf(180mg, 0. 370mmol)、リン酸三カリウム（水和物） (4. Og)及び 1, 4 ジォ キサン（60ml)の混合液を、窒素気流下、 90— 95°Cで 14時間撹拌した。反応液を 室温に冷却後、 3 ブロモ—6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピ リダジン（lOOmg, 0. 374mmol)、 [PdCl (dppf) ]/ジクロロメタン錯体（1： 1) (28 dppf (180mg, 0.370mmol), tripotassium phosphate (hydrate) (4. Og) and 1,4 dioxane (60ml) in a nitrogen stream at 90-95 ° C for 14 hours Stir. After cooling the reaction solution to room temperature, 3 bromo-6-[(cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine (lOOmg, 0.374 mmol), [PdCl (dppf)] / dichloromethane complex (1 : 1) (28
2  2
5mg, 0. 349mmol)及び dppf(205mg, 0. 370mmol)を追カロし、 90— 95。Cで 8 時間撹拌した。反応液を室温に冷却後、酢酸ェチルを加え、不溶物をセライトを用い てろ過で除去した。ろ液を減圧濃縮し、得られた残留物をフラッシュシリカゲルクロマ トグラフィ一に付し、ジクロロメタン:メタノール = 30: 1溶出部より得た分画を減圧濃縮 した。得られた固形物をへキサン/酢酸ェチル混合液（1： 1)で洗浄して標記化合物 (730mg, 75%)を得た。 Add 5 mg, 0.349 mmol) and dppf (205 mg, 0.370 mmol), 90-95. Stir at C for 8 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, and insolubles were removed by filtration using celite. The filtrate was concentrated under reduced pressure, the obtained residue was subjected to flash silica gel chromatography, and the fraction obtained from the dichloromethane: methanol = 30: 1 eluate was concentrated under reduced pressure. The resulting solid was washed with a hexane / ethyl acetate mixture (1: 1) to give the title compound (730 mg, 75%) was obtained.
NMR(CDC1 ) δ :0.19— 0.25(2H, m) , 0.50— 0.56 (2H, m) , 0.98— 1.0  NMR (CDC1) δ: 0.19- 0.25 (2H, m), 0.50- 0.56 (2H, m), 0.98- 1.0
3  Three
8(1H, m), 2.39 (3H, s) , 3.09 (2H, dd, J = 7.1, 5. 1Hz), 3.95(3H, s) , 4 .39-4.46(1H, m), 6.48(1H, d, J = 9.7Hz) , 7.58(1H, s) , 7.67(1H, d , J = 7.8Hz), 7.70(1H, d, J = 9.7Hz) , 7.94(1H, dm, J = 7.8Hz) , 8.01( 1H, s).  8 (1H, m), 2.39 (3H, s), 3.09 (2H, dd, J = 7.1, 5.1 Hz), 3.95 (3H, s), 4.39-4.46 (1H, m), 6.48 (1H , d, J = 9.7Hz), 7.58 (1H, s), 7.67 (1H, d, J = 7.8Hz), 7.70 (1H, d, J = 9.7Hz), 7.94 (1H, dm, J = 7.8Hz ), 8.01 (1H, s).
MS (LC) m/z： 337 (M+ + H) . MS (LC) m / z: 337 (M + + H).
(工程 3) 4— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル] 3—メチル安息香酸  (Step 3) 4- [6 -— [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] 3-methylbenzoic acid
[化 72] [Chemical 72]
Figure imgf000087_0001
4 [6 [ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2 b]ピリダジン 3 ィル] 3 メチル安息香酸 メチル エステノレ（150mg, 0.446mmol)及びメタノール（15 ml)の溶液に、 1N水酸化ナトリウム水溶液（1.5ml)を加え、加熱還流下に 5時間攪 拌した。反応液を室温に冷却し、 1N塩酸（1.5ml)を加えて中和後、減圧濃縮した。 得られた残留固形物を、水及びエーテルで洗浄後、減圧乾燥して標記化合物（123 mg, 86%)を得た。
Figure imgf000087_0001
4 [6 [(Cyclopropylmethyl) amino] imidazo [1, 2 b] pyridazine 3 yl] 3 methyl benzoate Methyl estenole (150 mg, 0.446 mmol) and methanol (15 ml) in a solution of 1N aqueous sodium hydroxide (1.5 ml) was added, and the mixture was stirred for 5 hours with heating under reflux. The reaction mixture was cooled to room temperature, neutralized with 1N hydrochloric acid (1.5 ml), and concentrated under reduced pressure. The obtained residual solid was washed with water and ether and then dried under reduced pressure to obtain the title compound (123 mg, 86%).
NMR(DMSO-d ) δ :0.14— 0.20 (2Η, m) , 0.40— 0.46 (2Η, m) , 0.97  NMR (DMSO-d) δ: 0.14— 0.20 (2Η, m), 0.40— 0.46 (2Η, m), 0.97
6  6
-1.06(1Η, m), 2.34 (3Η, s) , 2.97(2Η, dd, J = 6.6, 5.4Hz) , 6.75(1Η , d, J = 9.7Hz), 7.06(1Η, t, J = 5.3Hz) , 7.56(1Η, s) , 7.69(1Η, d, J = 7 .9Hz), 7.76(1Η, d, J = 9.7Hz) , 7.82(1Η, dd, J = 7.9, 1.8 Hz), 7.91— 7.93(1Η, m), 12.96(1Η, br s) .  -1.06 (1Η, m), 2.34 (3Η, s), 2.97 (2Η, dd, J = 6.6, 5.4Hz), 6.75 (1Η, d, J = 9.7Hz), 7.06 (1Η, t, J = 5.3 Hz), 7.56 (1Η, s), 7.69 (1Η, d, J = 7.9Hz), 7.76 (1Η, d, J = 9.7Hz), 7.82 (1Η, dd, J = 7.9, 1.8 Hz), 7.91 — 7.93 (1Η, m), 12.96 (1Η, br s).
MS (LC) m/z： 323 (M+ + H) . (工程 4) 4 [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル] N— [2 （ジメチルァミノ）ェチル] 3 メチルベンズアミド 2塩酸塩 MS (LC) m / z: 323 (M + + H). (Step 4) 4 [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] N— [2 (dimethylamino) ethyl] 3 methylbenzamide dihydrochloride
[0258] [化 73] [0258] [Chemical 73]
Figure imgf000088_0001
Figure imgf000088_0001
[0259] 4 [6 [ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィル] 3 メチル安息香酸（llOmg, 0.341mmol)、N, N ジメチルエチレンジァミン（0 .056ml, 0.51 Ommol)及び DMF (5. Oml)の混合 ί夜に、 4— (4, 6 ジメトキシ一 1, 3, 5 トリアジンー 2 ィノレ） 4ーメチノレモノレホリュウム クロリド（130mg, 0.52 Ommol)を加え、室温で 3日間攪拌した。反応混合物を減圧濃縮した。濃縮残渣を 分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニト リル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。濃縮残渣に 1N塩酸 (エタノー ノレ溶液）を加え、減圧濃縮して標記化合物（133mg, 84%)を得た。 [0259] 4 [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3 yl] 3 methylbenzoic acid (llOmg, 0.341mmol), N, N dimethylethylenediamine (0.056ml) , 0.51 Ommol) and DMF (5. Oml) on the night, add 4- (4,6 dimethoxy-1,3,5 triazine-2-inole) 4-methinoremonorephorium chloride (130 mg, 0.52 Ommol) And stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure. The concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. 1N Hydrochloric acid (ethanol solution) was added to the concentrated residue, and the mixture was concentrated under reduced pressure to obtain the title compound (133 mg, 84%).
NMR(DMSO-d ) δ :0.14— 0.19(2H, m) , 0.40— 0.49 (2H, m) , 0.95  NMR (DMSO-d) δ: 0.14— 0.19 (2H, m), 0.40— 0.49 (2H, m), 0.95
6  6
-1.06(1H, m), 2.34 (3H, s) , 2.84 (3H, s) , 2.85 (3H, s) , 2.96 (2H, dd , J = 6.6, 4.9Hz), 3.26-3.32 (2H, m) , 3.63— 3.70 (2H, m) , 7.24(1 H, d, J = 9.9Hz), 7.65(1H, d, J = 8.6Hz) , 7.79— 7.90 (2H, m) , 7.97( 1H, s), 8.05(1H, d, J = 9.9Hz) , 8.16(1H, s) , 8.95(1H, t, J = 5.4Hz) . MS(LC)m/z:393.6(M+ + H). -1.06 (1H, m), 2.34 (3H, s), 2.84 (3H, s), 2.85 (3H, s), 2.96 (2H, dd, J = 6.6, 4.9Hz), 3.26-3.32 (2H, m ), 3.63—3.70 (2H, m), 7.24 (1 H, d, J = 9.9Hz), 7.65 (1H, d, J = 8.6Hz), 7.79— 7.90 (2H, m), 7.97 (1H, s ), 8.05 (1H, d, J = 9.9Hz), 8.16 (1H, s), 8.95 (1H, t, J = 5.4Hz) MS (LC) m / z:. 393.6 (M + + H).
[実施例 12] 5— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン — 3 ィル] N— [2 (ジメチルァミノ）ェチル]チォフェン 2—カルボキサミド 2 塩酸塩  [Example 12] 5— [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine—3 yl] N— [2 (dimethylamino) ethyl] thiophene 2-carboxamide dihydrochloride
(工程 1) 5— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン— 3 ィル]チォフェン 2—力ルボン酸 (Step 1) 5- [6 — [(Cyclopropylmethyl) amino] imidazo [1, 2-b] pyridazine-3 Il] thiophene 2—power rubonic acid
[0260] [化 74]  [0260] [Chemical 74]
Figure imgf000089_0001
Figure imgf000089_0001
[0261] [実施例 2]に記載の 3—ブロモー 6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2 —b]ピリダジン（120mg, 0.449mmol)、 5 （ジヒドロキシボリル） 2 チォフェン カルボン酸（75mg, 0.436mmol)、テトラキス（トリフエニルホスフィン）パラジウム（0 ) (33mg, 0.029mmol)、炭酸セシウム（246mg, 0.755mmol)及び DMF/エタ ノール/水混合溶媒（7: 2: 3, 12ml)の混合液を、マイクロウエーブ反応装置 (Initia tor:Biotage社製）中、 130°Cで 5分間、攪拌下にマイクロウエーブを照射した。反応 液を室温に冷却後、減圧濃縮した。得られた濃縮残渣に飽和炭酸水素ナトリウム水 溶液を加え、酢酸ェチルで洗浄した。水層に濃塩酸を加えて中和後、室温で 14時 間攪拌した。生成した沈殿物を吸引ろ取して標記化合物 ½8mg, 48%)を得た。 NMR(DMSO-d ) δ :0.29— 0.34 (2Η, m) , 0.50— 0.56 (2Η, m) , 1.19 [0261] 3-Bromo 6-[(cyclopropylmethyl) amino] imidazo [1, 2 —b] pyridazine (120 mg, 0.449 mmol), 5 (dihydroxyboryl) 2 thiophene carboxylic acid described in [Example 2] 75mg, 0.436mmol), tetrakis (triphenylphosphine) palladium (0) (33mg, 0.029mmol), cesium carbonate (246mg, 0.755mmol) and DMF / ethanol / water mixed solvent (7: 2: 3, 12ml) The mixture was irradiated with microwaves in a microwave reactor (Initia tor: Biotage) at 130 ° C. for 5 minutes with stirring. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting concentrated residue and washed with ethyl acetate. Concentrated hydrochloric acid was added to the aqueous layer for neutralization, followed by stirring at room temperature for 14 hours. The resulting precipitate was collected by suction filtration to obtain the title compound (½8 mg, 48%). NMR (DMSO-d) δ: 0.29— 0.34 (2Η, m), 0.50— 0.56 (26, m), 1.19
6  6
-1.28(1Η, m), 3.26— 3.34 (2Η, m) , 6.79(1Η, d, J = 9.8Hz) , 7.38(1 Η, t, J = 5.4Hz), 7.71-7.76 (2Η, m) , 7.80(1Η, d, J = 9.8Hz) , 8.07( 1Η, s).  -1.28 (1Η, m), 3.26— 3.34 (2Η, m), 6.79 (1Η, d, J = 9.8Hz), 7.38 (1 Η, t, J = 5.4Hz), 7.71-7.76 (2Η, m) , 7.80 (1Η, d, J = 9.8Hz), 8.07 (1Η, s).
MS (LC) m/z :315 (M+ + H) . MS (LC) m / z: 315 (M + + H).
(工程 2) 5— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル] N— [2—（ジメチルァミノ）ェチル]チォフェン 2—カルボキサミド 2塩酸 塩  (Step 2) 5— [6 -— [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] N— [2- (dimethylamino) ethyl] thiophene 2-carboxamide dihydrochloride
[0262] [化 75]
Figure imgf000090_0001
5— [6 [ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2-b]ピリダジン 3 ィル]チ - 2 カルボン酸（65mg, 0.207mmol)、N, N ジメチルエチレンジアミ 035ml, 0.319mmol)及び DMF(5. Oml)の混合 ί夜に、 4— (4, 6 ジメトキ シ一 1, 3, 5 トリアジン一 2 ィル） 4 メチルモルホリニゥム クロリド（80mg, 0. 320mmol)を加え、室温で 14時間攪拌した。反応混合物を減圧濃縮した。濃縮残 渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセト 二トリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。濃縮残渣に 1N塩酸 (エタ ノール溶液）を加え、減圧濃縮した。得られた固形物をエーテルで洗浄して標記化合 物（58mg, 59%)を得た。 [0262] [Chemical 75]
Figure imgf000090_0001
5— [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3-yl] thi-2 carboxylic acid (65 mg, 0.207 mmol), N, N dimethylethylenediamine 035 ml, 0.319 mmol) and Mixing DMF (5. Oml) 4— (4, 6 Dimethoxy 1, 3, 5 Triazine 1 2 yl) 4 Methylmorpholinum chloride (80 mg, 0.320 mmol) was added at room temperature. For 14 hours. The reaction mixture was concentrated under reduced pressure. The concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile, water / formic acid), and the target fraction was concentrated under reduced pressure. 1N Hydrochloric acid (ethanol solution) was added to the concentrated residue, and the mixture was concentrated under reduced pressure. The obtained solid was washed with ether to obtain the title compound (58 mg, 59%).
NMR(DMSO-d ) δ :0.30— 0.35 (2Η, m) , 0.51— 0.57(2Η, m) , 1.18  NMR (DMSO-d) δ: 0.30- 0.35 (2Η, m), 0.51― 0.57 (2Η, m), 1.18
6  6
-1.28(1Η, m), 2.84 (3Η, s) , 2.85(3Η, s) , 3.24— 3.32 (4Η, m) , 3.5 9-3.65(2Η, m), 7.02(1Η, d, J = 9.9Hz) , 7.74(1Η, br s) , 7.83(1Η, d, J = 4. 1Hz), 7.90(1Η, d, J = 4.1Hz), 7.93(1H, d, J = 9.9Hz) , 8.32( 1H, s), 8.91(1H, t, J = 5.6Hz) .  -1.28 (1Η, m), 2.84 (3Η, s), 2.85 (3Η, s), 3.24— 3.32 (4 m, m), 3.5 9-3.65 (2Η, m), 7.02 (1Η, d, J = 9.9 Hz), 7.74 (1Η, br s), 7.83 (1 (, d, J = 4.1 Hz), 7.90 (1Η, d, J = 4.1Hz), 7.93 (1H, d, J = 9.9Hz), 8.32 ( 1H, s), 8.91 (1H, t, J = 5.6Hz).
IR(ATR)cm_1:3240, 3072, 2918, 2661, 2569, 2438, 1647, 1608, 1541 , 1504, 1456, 1286, 818, 748, 652, 611, 574. IR (ATR) cm _1 : 3240, 3072, 2918, 2661, 2569, 2438, 1647, 1608, 1541, 1504, 1456, 1286, 818, 748, 652, 611, 574.
MS (LC) m/z： 385 (M+ + H) . MS (LC) m / z: 385 (M + + H).
Anal. Calcd for C H N OS-2HC1-H 0:C, 48.00;H, 5.94; CI, 14.91  Anal.Calcd for C H N OS-2HC1-H 0: C, 48.00; H, 5.94; CI, 14.91
19 24 6 2  19 24 6 2
； N, 17.68;S, 6.74. Found :C, 48.05;H, 5.90; CI, 15.34;N, 17.48;S , 6.84.  N, 17.68; S, 6.74. Found: C, 48.05; H, 5.90; CI, 15.34; N, 17.48; S, 6.84.
[実施例 13] 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル]—N—[2—[(3R)—3 フルォロピロリジン 1ーィノレ]ェチノレ]ベンズァ ミド、 [Example 13] 4- [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3yl] —N— [2 — [(3R) —3 Fluoropyrrolidine 1-inore] ethinole] benzamide,
(工程 1) 3—ブロモー 6—[(tert ブトキシカルボニル）（シクロプロピルメチル）アミ ノ]イミダゾ [1, 2— b]ピリダジン  (Step 1) 3-Bromo-6-[(tert-butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine
[0264] [化 76] [0264] [Chem 76]
Figure imgf000091_0001
Figure imgf000091_0001
[0265] [実施例 2]に記載の 3 ブロモー 6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2 —b]ピリダジン（20.2g, 75.7mmol)、Boc 0(24.8g, 114mmol)、 DMAP (91 [0265] 3 Bromo-6 [(cyclopropylmethyl) amino] imidazo [1, 2 —b] pyridazine (20.2 g, 75.7 mmol), Boc 0 (24.8 g, 114 mmol), DMAP ( 91
2  2
6mg, 7.57mmol)及びジクロロメタン（200ml)の混合液を、加熱還流下に 2時間 攪拌した。反応液を室温に冷却後、 Boc 0(4.96g, 22.7mmol)を追加し、室温で  A mixture of 6 mg, 7.57 mmol) and dichloromethane (200 ml) was stirred with heating under reflux for 2 hours. After cooling the reaction solution to room temperature, Boc 0 (4.96 g, 22.7 mmol) was added, and
2  2
64時間攪拌した。反応混合物を減圧濃縮し、得られた残留物をシリカゲルカラムクロ マトグラフィ一で精製し、へキサン:酢酸ェチル =3: 1溶出部より得た分画を減圧濃 縮した。得られた固形物をへキサンで洗浄して標記化合物（25.9g, 93%)を得た。 NMR(CDC1 ) δ :0.39— 0.44 (2Η, m) , 0.48— 0.53 (2Η, m) , 1.29— 1.3  Stir for 64 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The fraction obtained from the hexane: ethyl acetate = 3: 1 eluate was concentrated under reduced pressure. The obtained solid was washed with hexane to obtain the title compound (25.9 g, 93%). NMR (CDC1) δ: 0.39— 0.44 (2 Η, m), 0.48— 0.53 (2 Η, m), 1.29— 1.3
3  Three
7(1Η, m), 1.54 (9Η, s) , 3.86 (2Η, d, J = 7.11Hz), 7.51(1H, d, J = 9.8 0Hz), 7.68(1H, s), 7.80(1H, d, J = 9.80Hz) .  7 (1Η, m), 1.54 (9Η, s), 3.86 (2Η, d, J = 7.11Hz), 7.51 (1H, d, J = 9.8 0Hz), 7.68 (1H, s), 7.80 (1H, d , J = 9.80Hz).
MS (LC) m/z： 367(M+ + H) . MS (LC) m / z: 367 (M + + H).
(工程 2) 4-[6-[ (tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダ ゾ [1, 2— b]ピリダジン 3 ィル]安息香酸 メチル エステル  (Step 2) 4- [6-[(tert-butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3-yl] benzoic acid methyl ester
[0266] [化 77]
Figure imgf000092_0001
[0266] [Chemical 77]
Figure imgf000092_0001
[0267] 3 ブロモー 6— [(tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダ ゾ [1, 2— b]ピリダジン（1· 5g, 4. lmmol)、 4ーメトキシカルボユルフェニルボロン 酸（1. lg, 6. lmmol)、 [PdCl (dppf) ]/ジクロロメタン錯体（1： 1) (163mg, 0. 2 [0267] 3 Bromo-6-[(tert-butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine (1 · 5 g, 4. lmmol), 4-methoxycarboylphenylboronic acid (1 lg, 6. lmmol), [PdCl (dppf)] / dichloromethane complex (1: 1) (163 mg, 0.2
2  2
mmol)、リン酸三カリウム（水和物）（3· 3g)及び 1, 4 ジォキサン/水混合液（9： 1 , 50ml)の混合液を、アルゴン雰囲気下、 85°Cで 18時間撹拌した。反応液を室温に 冷却後、酢酸ェチルを加え、不溶物をセライトを用いたろ過で除去した。ろ液を減圧 濃縮し、得られた残留物をフラッシュシリカゲルクロマトグラフィーに付し、へキサン： 酢酸ェチル =7: 13溶出部より得た分画を減圧濃縮して標記化合物（1. 6g, 92%) を得た。  mmol), tripotassium phosphate (hydrate) (3.3 g), and 1,4 dioxane / water mixture (9: 1, 50 ml) were stirred at 85 ° C. for 18 hours under an argon atmosphere. . The reaction solution was cooled to room temperature, ethyl acetate was added, and the insoluble material was removed by filtration using celite. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from the eluate of hexane: ethyl acetate = 7: 13 was concentrated under reduced pressure to give the title compound (1.6 g, 92 %).
MS (LC) m/z： 423 (M+ + H) .  MS (LC) m / z: 423 (M + + H).
(工程 3) 4-[6-[ (tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダ ゾ [1, 2— b]ピリダジン— 3 ィル]安息香酸  (Step 3) 4- [6-[(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] benzoic acid
[0268] [化 78] [0268] [Chemical 78]
Figure imgf000092_0002
Figure imgf000092_0002
[0269] 4 [6— [(tert ブトキシカルボ二. ミノ]イミダゾ [1, 2 —b]ピリダジンー3 ィル]安息香酸 メチル エステル（1.6g, 3.8mmol)、THF /メタノール混合液（4:1, 25ml)及び 1N水酸化ナトリウム水溶液（5· 7ml)の混合 液を、室温で 18時間、次いで 40°Cで 3時間攪拌した。反応液を室温に冷却後、減圧 濃縮した。濃縮残渣に水を加え、 1N塩酸を加えて弱酸性にした。析出した固形物を ろ取、減圧乾燥して標記化合物（1.5g, 97%)を得た。 [0269] 4 [6— [(tert Butoxycarboni. Mino] imidazo [1, 2 —B] pyridazine-3-yl] benzoic acid methyl ester (1.6 g, 3.8 mmol), THF / methanol mixture (4: 1, 25 ml) and 1N aqueous sodium hydroxide (5.7 ml) at room temperature. The mixture was stirred for 18 hours and then at 40 ° C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water was added to the concentrated residue, and 1N hydrochloric acid was added to make it weakly acidic. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (1.5 g, 97%).
NMR(DMSO-d ) δ :0.26— 0.31 (2Η, m) , 0.44— 0.48 (2Η, m) , 1.21  NMR (DMSO-d) δ: 0.26— 0.31 (2Η, m), 0.44— 0.48 (2Η, m), 1.21
6  6
-1.31(1Η, m), 1.48 (9Η, s) , 3.79 (2Η, d, J = 6.86Hz), 7.53(1H, d, J =9.56Hz), 8.04-8.06 (2H, m) , 8.17(1H, d, J = 9.80Hz) , 8.27(2H, dd, J = 6.74, 1.84Hz), 8.35(1H, d, J = 5.64Hz) , 13.00(1H, br s) . MS (LC) m/z： 409 (M+ + H) . -1.31 (1Η, m), 1.48 (9Η, s), 3.79 (2Η, d, J = 6.86Hz), 7.53 (1H, d, J = 9.56Hz), 8.04-8.06 (2H, m), 8.17 ( 1H, d, J = 9.80Hz), 8.27 (2H, dd, J = 6.74, 1.84Hz), 8.35 (1H, d, J = 5.64Hz), 13.00 (1H, br s) .MS (LC) m / z: 409 (M + + H ).
(工程 4) [2— [(3R)— 3 フルォロピロリジン 1 ィル]ェチル]力ルバミン酸 te rtーブチノレ エステノレ  (Step 4) [2 — [(3R) -3 fluoropyrrolidine 1 yl] ethyl] rubamic acid te rt-butinole Estenole
[化 79][Chemical 79]
Figure imgf000093_0001
Figure imgf000093_0001
(R)— (― )— 3 フルォロピロリジン塩酸塩（191mg, 1.20mmol)、 （2 ォキソ ェチノレ）力ルバミン酸 tert ブチノレ エステノレ（126mg, 1. OOmmol)、トリァセトキ シ水素ィ匕ホウ素ナ卜ジゥム（318mmol, 1.50mmol)、醉酸（0.086ml, 1.50mmo 1)及びジクロロメタン（5ml)の混合液を、窒素気流下、室温で 22時間攪拌した。反応 混合物に飽和炭酸水素ナトリウム水溶液を加え、室温で 10分攪拌後、クロ口ホルム で抽出した。抽出液を無水硫酸ナトリウムで乾燥、ろ過後、ろ液を減圧濃縮した。得ら れた残留物をシリカゲルカラムクロマトグラフィーに付し、クロ口ホルム：メタノール =2 0: 1溶出部より得た分画を減圧濃縮して標記化合物（21 lmg, 91%)を得た。 (R) — (—) — 3 Fluoropyrrolidine hydrochloride (191 mg, 1.20 mmol), (2 oxotinole) rubamic acid tert butinole estenole (126 mg, 1. OOmmol), triacetoxyhydrogen boron dimethyl (318 mmol, 1.50 mmol), a mixture of oxalic acid (0.086 ml, 1.50 mmo 1) and dichloromethane (5 ml) was stirred at room temperature for 22 hours under a nitrogen stream. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min and extracted with black mouth form. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the fraction obtained from the eluate of chloroformate: methanol = 2 0: 1 was concentrated under reduced pressure to obtain the title compound (21 lmg, 91%).
NMR(CDC1 ) δ :1.42 (9Η, s) , 1.97— 2.22 (3Η, m) , 2.41— 2.98 (5Η, NMR (CDC1) δ: 1.42 (9Η, s), 1.97— 2.22 (3Η, m), 2.41— 2.98 (5Η,
3  Three
m), 3. 18-3.31 (2Η, m) , 5.01— 5.14(1H, m) , 5.22— 5.35(1H, m) .m), 3.18-3.31 (2mm, m), 5.01-5.14 (1H, m), 5.22-5.35 (1H, m).
(工程 5) 2— [(3R)— 3—フルォロピロリジン 1 ィル]ェチルァミン 2塩酸塩 [0272] [化 80]
Figure imgf000094_0001
(Step 5) 2-[(3R)-3-Fluoropyrrolidine 1-yl] ethylamine dihydrochloride [0272] [Chemical 80]
Figure imgf000094_0001
[0273] [2— [ (3R)— 3 フルォロピロリジン 1 ィル]ェチル]力ルバミン酸 tert ブチ ノレ エステノレ（211mg, 0. 90mmol)及び 4N塩酸（1、 4 ジォキサン溶液）（6ml) の混合液を、室温で 2時間攪拌した。反応混合物を減圧濃縮し、得られた残留固形 物をエーテルで洗浄して標記化合物（142mg, 77%)を得た。 [0273] of [2 — [(3R) -3 fluoropyrrolidine 1yl] ethyl] rubamic acid tert butyno estenole (211 mg, 0.90 mmol) and 4N hydrochloric acid (1, 4 dioxane solution) (6 ml) The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residual solid was washed with ether to obtain the title compound (142 mg, 77%).
NMR (CD OD) δ : 2. 29— 2. 63 (2H, m) , 3. 37— 4. 09 (8H, m) , 5. 48 (1H  NMR (CD OD) δ: 2. 29— 2. 63 (2H, m), 3. 37— 4. 09 (8H, m), 5. 48 (1H
3  Three
, d, J= 52. 25Hz) .  , d, J = 52.25Hz).
(工程 6) 4— [6— [ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2—b]ピリダジンー3 ィル]—N— [2— [ (3R)— 3 フルォロピロリジン 1 ィル]ェチル]ベンズアミド [0274] [化 81]  (Step 6) 4— [6— [(Cyclopropylmethyl) amino] imidazo [1, 2—b] pyridazine-3 yl] —N— [2— [(3R) — 3 Fluoropyrrolidine 1 yl] Ethyl] benzamide [0274] [Chemical 81]
Figure imgf000094_0002
Figure imgf000094_0002
2— [ (3R)— 3 フルォロピロリジン 1 ィル]ェチルァミン 2塩酸塩（68mg, 0. 332mmol)、 [実施例 13]に記載の 4 [6— [ (tert ブトキシカルボニル）（シクロプ 口ピルメチル）ァミノ]イミダゾ [1 , 2 b]ピリダジン— 3 ィル]安息香酸（135mg, 0. 332mmol)、 EDC (95mg, 0. 497mmol)、 HOBt (45mg, 0. 332mmol)、 TEA (0. 093ml, 0. 663mmol)及び DMF (3ml)の混合液を、室温で 16時間攪拌した 。反応液をろ過して不溶物をろ別後、ろ液を減圧濃縮した。濃縮残渣にジクロ口メタ ン（5ml)及びトリフルォロ酢酸（5ml)を加え、室温で 1 · 5時間攪拌した。反応混合物 を減圧濃縮後、濃縮残渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。得 られた濃縮液に飽和炭酸水素ナトリウム水溶液を加え、液性をアルカリ性とした後、ク ロロホルムで抽出した。抽出液を飽和食塩水で洗浄、無水硫酸ナトリウム乾燥後、溶 媒を減圧濃縮した。得られた固形物をエーテルで洗浄して標記化合物（43mg, 30 %)を得た。 2— [(3R) — 3 Fluoropyrrolidine 1-yl] ethylamine dihydrochloride (68 mg, 0.32 mmol), 4 [6— [(tert-butoxycarbonyl) (cyclopentylmethyl) described in Example 13 ) Amino] imidazo [1, 2 b] pyridazine-3-yl] benzoic acid (135 mg, 0.332 mmol), EDC (95 mg, 0.497 mmol), HOBt (45 mg, 0.332 mmol), TEA (0.093 ml, A mixture of 0.663 mmol) and DMF (3 ml) was stirred at room temperature for 16 hours. The reaction mixture was filtered to remove insolubles, and the filtrate was concentrated under reduced pressure. Dichloromethane (5 ml) and trifluoroacetic acid (5 ml) were added to the concentrated residue, and the mixture was stirred at room temperature for 1.5 hours. Reaction mixture After concentration under reduced pressure, the concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the resulting concentrated liquid to make the liquid alkaline, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The obtained solid was washed with ether to obtain the title compound (43 mg, 30%).
NMR(CDC1 ) δ :0.28— 0.36 (2Η, m) , 0.57— 0.64 (2Η, m) , 1.13— 1.2  NMR (CDC1) δ: 0.28— 0.36 (2 Η, m), 0.57— 0.64 (2 Η, m), 1.13— 1.2
3  Three
2(1Η, m), 2.02-2.27(2Η, m) , 2.47— 2.55(1Η, m) , 2.70— 2.83(3Η , m), 2.93-3.06 (2Η, m) , 3.27(2Η, dd, J=7.08, 5.13Hz), 3.60 (2Η , dd, J=ll.11, 4.52Hz), 4.50— 4.53(1Η, m) , 5.11— 5.30(1Η, m) , 6 .49(1Η, d, J = 9.52Hz), 6.84(1Η, s) , 7.69(1Η, d, J = 9.52Hz), 7.87( 1Η, s), 7.88 (2Η, d, J = 8.79Hz), 8.21 (2Η, d, J=8.79Hz).  2 (1Η, m), 2.02-2.27 (2Η, m), 2.47—2.55 (1Η, m), 2.70—2.83 (3Η, m), 2.93-3.06 (2Η, m), 3.27 (2Η, dd, J = 7.08, 5.13Hz), 3.60 (2Η, dd, J = ll.11, 4.52Hz), 4.50-4.53 (1Η, m), 5.11― 5.30 (1Η, m), 6.49 (1Η, d, J = 9.52Hz), 6.84 (1Η, s), 7.69 (1Η, d, J = 9.52Hz), 7.87 (1Η, s), 7.88 (2Η, d, J = 8.79Hz), 8.21 (2Η, d, J = 8.79Hz).
MS (LC) m/z： 423 (M+ + H) . MS (LC) m / z: 423 (M + + H).
Anal. Calcd for C H FN O-0.25H 0:C, 64.69;H, 6.49;N, 19.68.  Anal.Calcd for C H FN O-0.25H 0: C, 64.69; H, 6.49; N, 19.68.
23 27 6 2  23 27 6 2
Found: C, 64.98;H, 6.40;N, 19.61.  Found: C, 64.98; H, 6.40; N, 19.61.
[実施例 14] 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン — 3 ィル] 2—フルォロ N— [3 (ジメチノレアミノ）プロパン一 2 -ィノレ]ベンズァ ミド 2塩酸塩  [Example 14] 4— [6 — [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine — 3 yl] 2 — Fluoro N— [3 (Dimethylolamino) propane-1-2-inole] benzamide Dihydrochloride
(工程 1) 4 [6— [(tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダ ゾ [ 1 , 2— b]ピリダジン 3 ィル] 3 フルォロベンズアルデヒド  (Step 1) 4 [6 — [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3 yl] 3 Fluorobenzaldehyde
[化 82] [Chemical 82]
Figure imgf000095_0001
[0277] [実施例 13]に記載の 3 ブロモー 6— [ (tert ブトキシカルボニル）（シクロプロピ ルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジン（380mg, 1. Ommol)、 3 フルオロー 4 ホルミルフエニルボロン酸（252mg, 1. 5mmol)、 [PdCl (dppf) ]/ジクロロメタ
Figure imgf000095_0001
[0277] 3 Bromo-6-[(tert-butoxycarbonyl) (cyclopropylmethyl) amino] imidazo described in [Example 13] [1,2-b] pyridazine (380 mg, 1. Ommol), 3 fluoro-4-formylphenyl Boronic acid (252 mg, 1.5 mmol), [PdCl (dppf)] / dichlorometa
2  2
ン錯体（1 : 1) (82mg, 0. lmmol)、リン酸三カリウム（水和物）（800mg)及び 1 , 4 ジォキサン/水混合液（9 : 1 , 15ml)の混合液を、アルゴン雰囲気下、 85°Cで 3時間 撹拌した。反応液を室温に冷却後、酢酸ェチルを加え、不溶物をセライトを用いたろ 過で除去した。ろ液を減圧濃縮し、得られた残留物をフラッシュシリカゲルクロマトグ ラフィ一に付し、へキサン:酢酸ェチル = 1： 1溶出部より得た分画を減圧濃縮して標 記化合物（390mg, 95%)を得た。  Complex of 1: 1 complex (1: 1) (82mg, 0.1ml), tripotassium phosphate (hydrate) (800mg) and 1,4 dioxane / water mixture (9: 1, 15ml) in argon atmosphere The mixture was stirred at 85 ° C for 3 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, and insolubles were removed by filtration using celite. The filtrate was concentrated under reduced pressure, the obtained residue was subjected to flash silica gel chromatography, and the fraction obtained from the eluate of hexane: ethyl acetate = 1: 1 was concentrated under reduced pressure to give the title compound (390 mg, 95 %).
MS (LC) m/z : 411 (M+ + H) .  MS (LC) m / z: 411 (M + + H).
(工程 2) 4 - [6 - [ (tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダ ゾ [ 1 , 2— b]ピリダジン 3 ィル] 2 フルォロ安息香酸  (Step 2) 4-[6-[(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3-yl] 2 Fluorobenzoic acid
[0278] [化 83] [0278] [Chemical 83]
Figure imgf000096_0001
Figure imgf000096_0001
[0279] 4 [6— [ (tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダゾ [1 , 2 —b]ピリダジンー3 ィル ]ー3 フルォロベンズアルデヒド（390mg, 0. 95mmol) 、 2 メチノレ一 2 フ、、テン（0. 503ml, 4. 75mmol)、リン酸二水素ナトリウム（172m g, 1. 43mmol)及び tert ブタノール/水混合液（4 : 1 , 10ml)の懸濁液に、亜塩 素酸ナトリウム（80%) (427mg, 3. 8mmol)を加え、室温で 3時間攪拌した。反応混 合液に 1N塩酸を加え、酢酸ェチルで抽出した。抽出液を無水硫酸ナトリウムで乾燥 後、減圧濃縮して標記化合物 (420mg, 100%)を得た。 NMR(DMSO-d ) δ :0.29— 0.34 (2H, m) , 0.44— 0.52 (2H, m) , 1.27[0279] 4 [6 — [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1, 2 —b] pyridazine-3 yl] -3 Fluorobenzaldehyde (390 mg, 0.995 mmol), 2 methylol In a suspension of 2F, Ten (0.503 ml, 4.75 mmol), sodium dihydrogen phosphate (172 mg, 1.43 mmol) and tert-butanol / water mixture (4: 1, 10 ml), subsalt Sodium iodate (80%) (427 mg, 3.8 mmol) was added, and the mixture was stirred at room temperature for 3 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (420 mg, 100%). NMR (DMSO-d) δ: 0.29— 0.34 (2H, m), 0.44— 0.52 (2H, m), 1.27
6 6
-1.35(1H, m), 1.50 (9H, s) , 3.80 (2H, d, J = 6.86Hz), 7.62(1H, d, J = 10.05Hz), 7.96-8.00(1H, m) , 8.05— 8.08(1H, m) , 8.15— 8.19( 1H, m), 8.21(1H, d, J=10.05Hz), 8.47(1H, s) .  -1.35 (1H, m), 1.50 (9H, s), 3.80 (2H, d, J = 6.86Hz), 7.62 (1H, d, J = 10.05Hz), 7.96-8.00 (1H, m), 8.05— 8.08 (1H, m), 8.15-8.19 (1H, m), 8.21 (1H, d, J = 10.05Hz), 8.47 (1H, s).
MS (LC) m/z： 427 (M+ + H) . MS (LC) m / z: 427 (M + + H).
(工程 3) 4-[6-[ (tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダ ゾ [ 1 , 2— b]ピリダジン 3 ィル]― 2—フルォロ N— [3 (ジメチルァミノ）プロパ ン— 2—ィル]ベンズアミド  (Step 3) 4- [6-[(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2-Fluoro N- [3 (dimethylamino) propan 2—yl] benzamide
[化 84] [Chemical 84]
Figure imgf000097_0001
4 [6— [(tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダゾ [1, 2 —b]ピリダジンー3 ィル ]ー2 フルォロ安息香酸（213mg, 0.5mmol)、 1ージメ チノレアミノー 2 プロピノレアミン（77mg, 0.75mmol) , EDC (144mg, 0.75mmol )、HOBt(68mg, 0.5mmol)、 TEA(0.417ml, 3. Ommol)及びジクロロメタン（1 5ml)の混合液を、室温で一晩攪拌した。反応混合液に水及び飽和炭酸水素ナトリ ゥム水溶液を加え、ジクロロメタンで抽出した。抽出液を無水硫酸ナトリウムで乾燥、 ろ過後、ろ液を減圧濃縮した。得られた残渣を分取 TLC (Merck, Silica— gel60, F , 2mm; 15%メタノール/ジクロロメタンで展開し、 30%メタノール/ジクロロメタ
Figure imgf000097_0001
4 [6— [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1, 2 —b] pyridazine-3 yl] -2 Fluorobenzoic acid (213 mg, 0.5 mmol), 1-dimethylolamino-2 propinoleamine (77 mg, 0.75 mmol), EDC (144 mg, 0.75 mmol), HOBt (68 mg, 0.5 mmol), TEA (0.417 ml, 3. Ommol) and dichloromethane (15 ml) were stirred at room temperature overnight. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC (Merck, Silica-gel60, F, 2 mm; developed with 15% methanol / dichloromethane, 30% methanol / dichlorometa
254 254
ンで溶出）で精製し、標記化合物（162mg, 63%)を得た。 The title compound (162 mg, 63%) was obtained.
NMR(CDC1 ) δ :0.30— 0.34 (2Η, m) , 0.49— 0.55(2Η, m) , 1.29— 1.3  NMR (CDC1) δ: 0.30— 0.34 (2 Η, m), 0.49— 0.55 (2 Η, m), 1.29— 1.3
3  Three
5(4Η, m), 1.55(9Η, s) , 2.30— 2.60(8Η, m) , 3.88 (2Η, d, J = 6.86Hz ), 4.25(1H, br s) , 7.08 (1H, br s) , 7.57(1H, d, J = 9.80Hz) , 7.89— 7.93 (2H, m), 7.99(1H, dd, J=13.73, 1.47Hz), 8.09(1H, s) , 8.17(1 H, t, J = 8.33Hz). 5 (4Η, m), 1.55 (9Η, s), 2.30— 2.60 (8Η, m), 3.88 (2Η, d, J = 6.86Hz ), 4.25 (1H, br s), 7.08 (1H, br s), 7.57 (1H, d, J = 9.80Hz), 7.89— 7.93 (2H, m), 7.99 (1H, dd, J = 13.73, 1.47 Hz), 8.09 (1H, s), 8.17 (1 H, t, J = 8.33Hz).
MS (LC) m/z :511 (M+ + H) . MS (LC) m / z: 511 (M + + H).
(工程 4) 4— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 —ィル] 2 フルォロ N— [3 (ジメチルァミノ）プロパン一 2 ィル]ベンズアミド 2塩酸塩  (Step 4) 4— [6— [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine-3 —yl] 2 Fluoro N— [3 (Dimethylamino) propane-1-yl] benzamide dihydrochloride
[0282] [化 85] [0282] [Chemical 85]
Figure imgf000098_0001
Figure imgf000098_0001
[0283] 4 [6— [(tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダゾ [1, 2 —b]ピリダジンー3 ィル ]ー2 フルオロー N— [3 （ジメチルァミノ）プロパンー2 ィル]ベンズアミド（162mg, 0.32mmol)及び 4N塩酸（1, 4 ジォキサン溶液）（ 15ml)の混合液を、室温で 6時間攪拌した。反応液を減圧濃縮し、少量のエーテル を加えて静置した。析出した固形物をろ取して標記化合物（147mg, 95%)を得た。 [0283] 4 [6— [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1, 2 —b] pyridazine-3 yl] -2 Fluoro N— [3 (dimethylamino) propane-2-yl] benzamide ( A mixed solution of 162 mg, 0.32 mmol) and 4N hydrochloric acid (1,4 dioxane solution) (15 ml) was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, a small amount of ether was added, and the mixture was allowed to stand. The precipitated solid was collected by filtration to obtain the title compound (147 mg, 95%).
NMR(DMSO-d ) δ :0.27— 0.32 (2Η, m) , 0.49— 0.58 (2Η, m) , 1.07  NMR (DMSO-d) δ: 0.27— 0.32 (2Η, m), 0.49— 0.58 (2Η, m), 1.07
6  6
-1.27 {AH, m), 2.73— 2.86 (6H, m) , 3.12— 3.71 (5H, m) , 7.23(1H, d, J = 9.80Hz), 7.92-8.11 (4H, m) , 8.23(1H, dd, J=12.50, 1.47Hz) , 8.52-8.55(1H, m) , 9.93(1H, br s) .  -1.27 (AH, m), 2.73— 2.86 (6H, m), 3.12— 3.71 (5H, m), 7.23 (1H, d, J = 9.80Hz), 7.92-8.11 (4H, m), 8.23 (1H , dd, J = 12.50, 1.47Hz), 8.52-8.55 (1H, m), 9.93 (1H, br s).
IR(ATR)cm_1:3048, 2670, 1621, 1608, 1508. IR (ATR) cm _1 : 3048, 2670, 1621, 1608, 1508.
MS (LC) m/z :411 (M+ + H) . MS (LC) m / z: 411 (M + + H).
Anal. Calcd for C H FN 0-2HC1-2H 0:C, 50.87;H, 6.40; CI, 13.6  Anal.Calcd for C H FN 0-2HC1-2H 0: C, 50.87; H, 6.40; CI, 13.6
22 27 6 2  22 27 6 2
5;F, 3.66;N, 16. 18. Found :C, 51.08;H, 6.45;C1, 13.76;F, 3.84;N , 15. 96. 5; F, 3.66; N, 16. 18. Found: C, 51.08; H, 6.45; C1, 13.76; F, 3.84; N , 15. 96.
[実施例 15] 4— [6— [ (シクロプロピルメチル)ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィル ]ー2 フルオロー N メチノレー N—[2 （ジメチルァミノ）ェチノレ]ベンズ アミド 2塩酸塩  [Example 15] 4— [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3 yl] -2 Fluoro-N Methylenole N— [2 (Dimethylamino) ethinole] benzamide dihydrochloride
(工程 1) 4 [6— [ (tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダ ゾ [1 , 2— b]ピリダジンー3 ィル ]ー2 フルオロー N メチルー N—[2—(ジメチル ァミノ）ェチル]ベンズアミド  (Step 1) 4 [6— [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2 Fluoro-N-methyl-N- [2- (dimethylamino) ethyl Benzamide
[化 86]  [Chemical 86]
Figure imgf000099_0001
Figure imgf000099_0001
[実施例 14]に記載の 4 [6— [ (tert ブトキシカルボニル）（シクロプロピルメチル )ァミノ]イミダゾ [ 1 , 2 b]ピリダジン— 3 ィル] 2 フルォロ安息香酸（ 150mg, 0. 35mmol)、N, N, N，一トリメチルエチレンジァミン（57mg, 0. 56mmol)、 EDC (lOOmg, 0. 52mmol)、 HOBt (47mg, 0. 35mmol)、 TEA (0. 146ml, 1. lm mol)及びジクロロメタン（10ml)の混合液を、室温でー晚攪拌した。反応混合液に水 及び飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。抽出液を無水 硫酸ナトリウムで乾燥、ろ過後、ろ液を減圧濃縮した。得られた残渣を分取 TLC (Me rck, Silica— gel60, F , 1mm ; 20%メタノール/ジクロロメタンで展開し、 30%メ 4 [6 — [(tert-butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2b] pyridazine-3-yl] 2 fluorobenzoic acid (150 mg, 0.35 mmol) described in [Example 14], N, N, N, monotrimethylethylenediamine (57 mg, 0.56 mmol), EDC (lOOmg, 0.52 mmol), HOBt (47 mg, 0.35 mmol), TEA (0.146 ml, 1. lm mol) and A mixture of dichloromethane (10 ml) was stirred at room temperature. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was developed with preparative TLC (Me rck, Silica-gel60, F, 1 mm; 20% methanol / dichloromethane, 30%
254  254
タノール/ジクロロメタンで溶出）で精製し、標記化合物（130mg, 73%)を得た。 NMR (CDC1 ) δ : 0. 29— 0. 34 (2Η, m) , 0. 47— 0. 52 (2Η, m) , 1. 29— 1. 3 The title compound (130 mg, 73%) was obtained by purification with elution with methanol / dichloromethane. NMR (CDC1) δ: 0. 29— 0.34 (2Η, m), 0.47— 0.52 (2Η, m), 1. 29— 1. 3
3  Three
2 (1Η, m) , 1. 55 (9Η, s) , 2. 09 (3Η, s) , 2. 36 (3Η, s) , 2. 40— 2. 45 (1Η, m) , 2. 62 - 2. 67 (1Η, m) , 3. 02 and 3. 15 (total 3Η, each s) , 3. 34— 3.37(1H, m), 3.70— 3.72(1H, m) , 3.86 (2H, d, J = 6.84Hz) , 7.43— 7 .57(2H, m), 7.81— 7.99(3H, m) , 8.04(1H, s) . 2 (1Η, m), 1.55 (9Η, s), 2.09 (3Η, s), 2.36 (3Η, s), 2.40— 2.45 (1Η, m), 2.62 -2. 67 (1Η, m), 3. 02 and 3. 15 (total 3Η, each s), 3. 34— 3.37 (1H, m), 3.70— 3.72 (1H, m), 3.86 (2H, d, J = 6.84Hz), 7.43— 7.57 (2H, m), 7.81— 7.99 (3H, m), 8.04 ( 1H, s).
MS (LC) m/z :511 (M+ + H) . MS (LC) m / z: 511 (M + + H).
(工程 2) 4— [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 -ィル]— 2—フルォロ N メチル N— [ 2— (ジメチルァミノ）ェチル]ベンズアミド (Step 2) 4— [6 [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine-3-yl] — 2-Fluoro N methyl N— [2— (Dimethylamino) ethyl] benzamide
2塩酸塩 Dihydrochloride
[化 87] [Chemical 87]
Figure imgf000100_0001
4 [6— [(tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダゾ [1, 2 —b]ピリダジンー3 ィル ]ー2 フルオロー N メチルー N— [2 （ジメチルァミノ） ェチル]ベンズアミド（130mg, 0.25mmol)及び 4N塩酸（1, 4 ジォキサン溶液）（ 10ml)の混合液を、室温で 3時間攪拌した。反応液を減圧濃縮した後、残渣を少量 のメタノールに溶解し、エーテルを加えて静置した。析出した固形物をろ取して標記 化合物（lOOmg, 96%)を得た。
Figure imgf000100_0001
4 [6 — [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1, 2 —b] pyridazine-3 yl] -2 Fluoro-N-methyl-N— [2 (dimethylamino) ethyl] benzamide (130 mg, 0.25 mmol ) And 4N hydrochloric acid (1,4 dioxane solution) (10 ml) were stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in a small amount of methanol, ether was added and the mixture was allowed to stand. The precipitated solid was collected by filtration to obtain the title compound (lOOmg, 96%).
NMR(DMSO-d ) δ :0.28— 0.30 (2Η, m) , 0.52— 0.54 (2Η, m) , 1.15  NMR (DMSO-d) δ: 0.28— 0.30 (2Η, m), 0.52— 0.54 (2Η, m), 1.15
6  6
-1.22(1Η, m), 2.85— 2.86 (6Η, m) , 2.93— 3.40 (7Η, m) , 3.87— 3. 89 (2Η, m), 7.24(1Η, d, J=10.05Hz), 7.78— 7.80(1H, m) , 7.97— 8. 25 (4H, m), 8.53(1H, s) .  -1.22 (1Η, m), 2.85— 2.86 (6Η, m), 2.93— 3.40 (7Η, m), 3.87— 3.89 (2Η, m), 7.24 (1Η, d, J = 10.05Hz), 7.78 — 7.80 (1H, m), 7.97— 8. 25 (4H, m), 8.53 (1H, s).
IR(ATR)cm_1:3257, 2572, 2472, 1621, 1608, 1504. IR (ATR) cm _1 : 3257, 2572, 2472, 1621, 1608, 1504.
MS (LC) m/z :411 (M+ + H) . MS (LC) m / z: 411 (M + + H).
Anal. Calcd for C H FN OS -2HC1-H 0:C, 52.70;H, 6.23; CI, 14.  Anal.Calcd for C H FN OS -2HC1-H 0: C, 52.70; H, 6.23; CI, 14.
22 27 6 2 2  22 27 6 2 2
14;F, 3.79;N, 16.76. Found :C, 52.64;H, 5.97;C1, 14.49;F, 3.58; N, 16.60. 14; F, 3.79; N, 16.76.Found: C, 52.64; H, 5.97; C1, 14.49; F, 3.58; N, 16.60.
[実施例 16] 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン — 3 ィル]― 2—フルォロ N— [[(2S)— 1—メチルピロリジン 2 ィル]メチル] ベンズアミド 2塩酸塩  [Example 16] 4— [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine—3 yl] —2-Fluoro N — [[(2S) —1-methylpyrrolidine 2 Lu] methyl] benzamide dihydrochloride
(工程 1) (2S) 2— [ [ [ (ベンジルォキシ)カルボニル]ァミノ]メチル]ピロリジン 1 一力ノレボン酸 tert ブチノレ エステノレ  (Step 1) (2S) 2 -— [[[(Benzyloxy) carbonyl] amino] methyl] pyrrolidine 1 One strength norevonic acid tert Butinole Estenole
[0288] [化 88] [0288] [Chemical 88]
Figure imgf000101_0001
Figure imgf000101_0001
[0289] (2S)— 2—（アミノメチル）ピロリジン 1一力ルボン酸 tert ブチル エステル（1 . Og, 5. Ommol)及びジクロロメタン（20ml)の混合液に、飽和炭酸水素ナトリウム水 溶液（20ml)を加え、攪拌下にクロロギ酸べンジル（1. lml, 8. Ommol)を滴下した 。反応混合液を室温で一晩攪拌後、ジクロロメタンで抽出した。抽出液を無水硫酸ナ トリウムで乾燥、ろ過後、ろ液を減圧濃縮した。得られた残渣をフラッシュシリカゲルク 口マトグラフィ一に付し、へキサン:酢酸ェチル =4: 1溶出部より得た分画を減圧濃縮 して標記化合物（1.3g, 79%)を得た。 [0289] (2S) -2- (Aminomethyl) pyrrolidine 1 Monolithic rubonic acid tert butyl ester (1. Og, 5. Ommol) and dichloromethane (20 ml) mixed with saturated aqueous sodium hydrogen carbonate solution (20 ml) Benzyl chloroformate (1. lml, 8. Ommol) was added dropwise with stirring. The reaction mixture was stirred at room temperature overnight and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane: ethyl acetate = 4: 1 eluate was concentrated under reduced pressure to obtain the title compound (1.3 g, 79%).
NMR(CDC1 ) δ :1.45(9H, s) , 1.69— 1.99 (4H, m) , 3.21— 3.40 (3H,  NMR (CDC1) δ: 1.45 (9H, s), 1.69— 1.99 (4H, m), 3.21— 3.40 (3H,
3  Three
m), 3.84-3.97(1H, m) , 4.70(1H, d, J = 4.66Hz), 5.10(2H, s) , 7.27 -7.40 (5H, m).  m), 3.84-3.97 (1H, m), 4.70 (1H, d, J = 4.66Hz), 5.10 (2H, s), 7.27-7.40 (5H, m).
(工程 2) [[(2S) 1 メチルピロリジンー2—ィル]メチル]力ルバミン酸 ベンジル エステノレ  (Step 2) [[(2S) 1 Methylpyrrolidine-2-yl] methyl] strength rubamate Benzyl Estenole
[0290] [化 89] [0290] [Chemical 89]
Figure imgf000101_0002
[0291] (2S) 2— [ [ [ (ベンジルォキシ）カルボニル]ァミノ]メチル]ピロリジン 1 カルボ ン酸 tert ブチル エステル（1. 3g, 3. 9mmol)及び 4N塩酸（1, 4 ジォキサン 溶液）（30ml)の混合液を、室温で 2. 5時間攪拌した。反応液を減圧濃縮した。得ら れた濃縮残渣をメタノール (40ml)に溶解し、 37%ホルムアルデヒド水溶液（2ml)、 酢酸（0.480ml, 8. Ommol)及びシァノ水素化ホウ素ナトリウム（740mg, 11. 7m mol)を加え、室温で一晩攪拌した。反応液に水及び飽和炭酸水素ナトリウム水溶液 を加え、ジクロロメタンで抽出した。抽出液を無水硫酸ナトリウムで乾燥、ろ過後、ろ液 を減圧濃縮して標記化合物（1. Og, 100%)を得た。
Figure imgf000101_0002
[0291] (2S) 2-[[[[(Benzyloxy) carbonyl] amino] methyl] pyrrolidine 1 carboxylic acid tert butyl ester (1.3 g, 3.9 mmol) and 4N hydrochloric acid (1,4 dioxane solution) (30 ml) The mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure. The obtained concentrated residue was dissolved in methanol (40 ml), 37% aqueous formaldehyde solution (2 ml), acetic acid (0.480 ml, 8. Ommol) and sodium cyanoborohydride (740 mg, 11.7 mmol) were added, and room temperature was added. Stir overnight. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (1. Og, 100%).
NMR(CDC1 ) δ :1. 54— 1. 90 (4Η, m) , 2. 15— 2. 38 (5Η, m) , 3.01— 3.0  NMR (CDC1) δ: 1.54— 1. 90 (4Η, m), 2. 15— 2. 38 (5Η, m), 3.01— 3.0
3  Three
5(1Η, m), 3. 13-3. 17(1Η, m) , 3. 38— 3.47(1Η, m) , 5. 07— 5. 16(2Η , m), 5. 19-5. 28(1Η, m) , 7. 27— 7.40 (5Η, m) .  5 (1Η, m), 3.13-3. 17 (1Η, m), 3.38—3.47 (1Η, m), 5.07—5.16 (2 (, m), 5. 19-5. 28 (1Η, m), 7. 27- 7.40 (5Η, m).
(工程 3) (2S)— 2 アミノメチルー 1 メチルピロリジン  (Step 3) (2S) — 2 aminomethyl-1 methylpyrrolidine
[0292] [化 90] [0292] [Chemical 90]
Figure imgf000102_0001
Figure imgf000102_0001
[0293] [[(2S)— 1 メチルピロリジンー2—ィル]メチル」力ルバミン酸 ベンジル エステ ノレ（1. 0g, 4. Ommol)及びエタノール（30ml)の溶液に、 10%水酸化パラジウム炭 素（300mg)を加えて、水素雰囲気下（1気圧）、室温で一晩攪拌した。触媒をろ別後 、再び水酸化パラジウム炭素（500mg)を加えて、水素雰囲気下（1気圧）、室温で一 晚攪拌した。触媒をろ別後、ろ液を減圧濃縮して標記化合物 (440mg, 96%)を得 た。 [0293] [[(2S) -1 Methylpyrrolidin-2-yl] methyl ”strength Ruby Estamine (1.0 g, 4. Ommol) and ethanol (30 ml) in a solution of 10% palladium hydroxide charcoal Elementary (300 mg) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (1 atm). After the catalyst was filtered off, palladium hydroxide carbon (500 mg) was added again, and the mixture was stirred at room temperature under a hydrogen atmosphere (1 atm). After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to obtain the title compound (440 mg, 96%).
MS (LC) m/z :115 (M+ + H) .  MS (LC) m / z: 115 (M + + H).
(工程 4) 4-[6-[ (tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダ ゾ [1, 2— b]ピリダジンー3 ィル ]ー2 フルオロー N—[[(2S)—1- ジン 2—ィル]メチル]ベンズアミド  (Step 4) 4- [6-[(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2 Fluoro-N — [[(2S) -1-Gyne 2—yl] methyl] benzamide
[0294] [化 91]
Figure imgf000103_0001
[0294] [Chemical 91]
Figure imgf000103_0001
[0295] [実施例 14]に記載の 4 [6— [(tert ブトキシカルボ二， [0295] 4 [6 — [(tert-butoxycarbodi,
)ァミノ]イミダゾ [ 1 , 2— b]ピリダジン— 3—ィル]— 2—フルォロ安息香酸（213mg, 0.5mmol)、 （2S)— 2 （アミノメチノレ） 1ーメチノレピロリジン（114mg, 1. Ommol )、 EDC(144mg, 0.75mmol)、 HOBt(68mg, 0.5mmol)、 TEA(0.417ml, 3 . Ommol)及びジクロロメタン（15ml)の混合液を、室温で一晩攪拌した。反応混合 液に水及び飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。抽出 液を無水硫酸ナトリウムで乾燥、ろ過後、ろ液を減圧濃縮した。得られた残渣を分取 TLC (Merck, Silica— gel60, F , 2mm; 15%メタノール/ジクロロメタンで展開  ) Amino] imidazo [1,2-b] pyridazine-3-yl] -2-fluorobenzoic acid (213mg, 0.5mmol), (2S) -2 (aminomethinore) 1-methinorepyrrolidine (114mg, 1. Ommol) ), EDC (144 mg, 0.75 mmol), HOBt (68 mg, 0.5 mmol), TEA (0.417 ml, 3.0 mmol) and dichloromethane (15 ml) were stirred overnight at room temperature. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Preparative residue obtained TLC (Merck, Silica-gel60, F, 2mm; developed with 15% methanol / dichloromethane
254  254
し、 30%メタノール/ジクロロメタンで溶出）で精製し、標記化合物（105mg, 40%) を得た。  And eluted with 30% methanol / dichloromethane) to give the title compound (105 mg, 40%).
NMR(CDC1 ) δ :0.30— 0.34 (2Η, m) , 0.49— 0.54 (2Η, m) , 1.26— 1.3  NMR (CDC1) δ: 0.30— 0.34 (2 Η, m), 0.49— 0.54 (2 Η, m), 1.26— 1.3
3  Three
5(1Η, m), 1.57(9Η, s) , 1.68— 2.54(11Η, m) , 3.86— 3.88 (4Η, m) , 7 .57(1Η, d, J=10.05Hz), 7.88— 8.18(5Η, m) .  5 (1Η, m), 1.57 (9Η, s), 1.68− 2.54 (11Η, m), 3.86− 3.88 (4Η, m), 7.57 (1Η, d, J = 10.05Hz), 7.88− 8.18 ( 5Η, m).
MS (LC) m/z： 523 (M+ + H) . MS (LC) m / z: 523 (M + + H).
(工程 5) 4— [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ーィル ]ー2—フルオロー N—[[(2S)—1ーメチルピロリジンー2—ィノレ]メチノレ]ベン ズアミド 2塩酸塩  (Step 5) 4- [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2-fluoro-N-[[(2S) -1-methylpyrrolidine-2-inole] methinole ] Benzamide dihydrochloride
[0296] [化 92]
Figure imgf000104_0001
[0296] [Chem 92]
Figure imgf000104_0001
[0297] 4—[6—[(tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダゾ [1, 2 b]ピリダジンー3—ィル]ー2 フルォローN—[[(2S)—lーメチルピロリジンー2 ィル]メチル]ベンズアミド（105mg, 0.2mmol)及び 4N塩酸（1, 4 ジォキサン 溶液）（15ml)の混合液を、室温で 6.5時間攪拌した。反応液を減圧濃縮し、少量の エーテルを加えて静置した。析出した固形物をろ取、減圧乾燥して標記化合物（100 mg, 99%)を得た。 [0297] 4— [6 — [(tert Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1, 2 b] pyridazine-3-yl] -2 Fluoro N — [[(2S) —l-methylpyrrolidine A mixture of [2yl] methyl] benzamide (105 mg, 0.2 mmol) and 4N hydrochloric acid (1,4 dioxane solution) (15 ml) was stirred at room temperature for 6.5 hours. The reaction mixture was concentrated under reduced pressure, a small amount of ether was added, and the mixture was allowed to stand. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (100 mg, 99%).
NMR(DMSO-d ) δ :0.29— 0.37 (2Η, m) , 0.51— 0.61 (2Η, m) , 1.07  NMR (DMSO-d) δ: 0.29— 0.37 (2 Η, m), 0.51— 0.61 (2 Η, m), 1.07
6  6
-1.22(1Η, m), 1.83— 2.26 (4Η, m) , 2.82— 4.23 (9Η, m) , 7.25(1Η, d, J = 9.80Hz), 7.87-8.27(5Η, m) , 8.56(1Η, s) , 8.84(1Η, br s) , 10 .63(1Η, br s) .  -1.22 (1Η, m), 1.83― 2.26 (4Η, m), 2.82― 4.23 (9Η, m), 7.25 (1Η, d, J = 9.80Hz), 7.87-8.27 (5Η, m), 8.56 (1Η , s), 8.84 (1Η, br s), 10.63 (1Η, br s).
IR(ATR)cm_1:3220, 3058, 2956, 2624, 2493, 1654, 1621, 1506. IR (ATR) cm _1 : 3220, 3058, 2956, 2624, 2493, 1654, 1621, 1506.
MS (LC) m/z： 423 (M+ + H) . MS (LC) m / z: 423 (M + + H).
[実施例 17] 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン — 3 ィル]—2 フルォロ一 N メチノレ一 N— (1—メチルピロリジン一 3 ィノレ）ベン ズアミド 2塩酸塩  [Example 17] 4— [6 — [(Cyclopropylmethyl) amino] imidazo [1, 2—b] pyridazine — 3 yl] —2 Fluoro N Methinole N— (1-Methylpyrrolidine 1 3 Ino) Benzamide dihydrochloride
(工程 1) 4 [6— [(tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダ ゾ [1, 2— b]ピリダジンー3—ィル ]ー2—フルオロー N メチルー N—(l—メチルビ 口リジン 3—ィル）ベンズアミド  (Step 1) 4 [6 -— [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2-fluoro-N methyl-N- (l-methylbiphenyl lysine 3—yl) benzamide
[0298] [化 93]
Figure imgf000105_0001
[0298] [Chemical 93]
Figure imgf000105_0001
[0299] [実施例 14]に記載の 4 [6— [(tert ブトキシカルボ二， [0299] 4 [6 — [(tert-butoxycarbodi,
)ァミノ]イミダゾ [ 1 , 2 b]ピリダジン— 3 ィル] 2 フルォロ安息香酸（ 150mg, 0. 35mmol)、 3— (N メチルァミノ）一 1—メチルピロリジン（64mg, 0. 56mmol) 、EDC(100mg, 0. 52mmol)、 HOBt (47mg, 0. 35mmol)、 TEA(0. 146ml, 1. 05mmol)及びジクロロメタン（10ml)の混合液を、室温で一晩攪拌した。反応混 合液に水及び飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。抽 出液を無水硫酸ナトリウムで乾燥、ろ過後、ろ液を減圧濃縮した。得られた残渣を分 取 TLC(Merck, Silica— gel60, F , 1mm; 10%メタノール/ジクロロメタンで展  ) Amino] imidazo [1,2b] pyridazine-3yl] 2 fluorobenzoic acid (150mg, 0.35mmol), 3- (N-methylamino) mono-1-methylpyrrolidine (64mg, 0.56mmol), EDC (100mg) , 0.52 mmol), HOBt (47 mg, 0.35 mmol), TEA (0.146 ml, 1.05 mmol) and dichloromethane (10 ml) were stirred at room temperature overnight. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by preparative TLC (Merck, Silica-gel 60, F, 1 mm; and expanded with 10% methanol / dichloromethane.
254  254
開し、 30%メタノール/ジクロロメタンで溶出）で精製し、標記化合物（135mg, 74% And elute with 30% methanol / dichloromethane) to give the title compound (135 mg, 74%
)を得た。 )
NMR(CDC1 ) δ :0. 27— 0. 34 (2Η, m) , 0.49— 0. 51 (2Η, m) , 1. 26— 1. 3  NMR (CDC1) δ: 0. 27— 0.34 (2Η, m), 0.49— 0.51 (2Η, m), 1. 26— 1.3
3  Three
4(1Η, m), 1. 54 (9Η, s) , 1. 61-1. 98 (2Η, m) , 2. 24— 2. 76 (7Η, m) , 2. 98-3. 13(3Η, m), 3. 86 (2Η, d, J = 6. 84Hz) , 4. 32— 4. 35(1H, m) , 7. 3 8-7. 56 (2H, m), 7. 81— 7. 95(3H, m) , 8.04(1H, s) .  4 (1Η, m), 1. 54 (9Η, s), 1. 61-1.98 (2Η, m), 2. 24— 2.76 (7Η, m), 2. 98-3. 13 ( 3Η, m), 3.86 (2Η, d, J = 6.84Hz), 4.32— 4.35 (1H, m), 7. 3 8-7. 56 (2H, m), 7. 81 — 7. 95 (3H, m), 8.04 (1H, s).
MS (LC) m/z： 523 (M+ + H) . MS (LC) m / z: 523 (M + + H).
(工程 2) 4— [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 -ィル]— 2—フルォロ N メチル N— ( 1—メチルピロリジン 3—ィノレ）ベンズ アミド 2塩酸塩  (Step 2) 4— [6 [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine-3-yl] — 2-Fluoro N methyl N— (1-methylpyrrolidine 3-inore) benzamide 2 Hydrochloride
[0300] [化 94]
Figure imgf000106_0001
[0300] [Chemical 94]
Figure imgf000106_0001
[0301] 4 [6
Figure imgf000106_0002
[1, 2[0301] 4 [6
Figure imgf000106_0002
[1, 2
—b]ピリダジンー3—ィル ]ー2 フルオロー N—メチルー N—(l メチルピロリジン — 3 ィル）ベンズアミド（135mg, 0.25mmol)及び 4N塩酸（1, 4 ジォキサン溶 液）（10ml)の混合液を、室温で 3時間攪拌した。反応液を減圧濃縮し、少量のエー テルを加えて静置した。析出した固形物をろ取、減圧乾燥して標記化合物（70mg, 57%)を得た。 —B] Pyridazine-3-yl] -2 Mixture of fluoro-N-methyl-N- (l methylpyrrolidine-3 yl) benzamide (135 mg, 0.25 mmol) and 4N hydrochloric acid (1,4 dioxane solution) (10 ml) Was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, a small amount of ether was added, and the mixture was allowed to stand. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (70 mg, 57%).
NMR(DMSO-d ) δ :0.28— 0.34 (2Η, m) , 0.51— 0.57(2Η, m) , 1.14  NMR (DMSO-d) δ: 0.28— 0.34 (2 Η, m), 0.51— 0.57 (2 Η, m), 1.14
6  6
-1.23(1Η, m), 2.15— 2.34 (2Η, m) , 2.68— 4.83(13Η, m) , 7.28(1Η , d, J = 9.80Hz), 7.58-7.65(1Η, m) , 8.01— 8.27(3Η, m) , 8.58(1Η, d, J = 7. 11Hz), 11.01-11.69(1Η, m) .  -1.23 (1Η, m), 2.15― 2.34 (2Η, m), 2.68― 4.83 (13Η, m), 7.28 (1Η, d, J = 9.80Hz), 7.58-7.65 (1Η, m), 8.01― 8.27 (3Η, m), 8.58 (1Η, d, J = 7. 11Hz), 11.01-11.69 (1Η, m).
IR(ATR)cm— 3222, 2460, 1623, 1606, 1504.  IR (ATR) cm— 3222, 2460, 1623, 1606, 1504.
MS (LC) m/z： 423 (M+ + H) . MS (LC) m / z: 423 (M + + H).
[実施例 18] 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン — 3 ィル] 2 フルォロ一 N— [[(2S, 4S)—4 フルォロピロリジン一 2 ィル]メ チル]ベンズアミド  [Example 18] 4— [6 — [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine—3 yl] 2 Fluoro N — [[(2S, 4S) -4 Fluoropyrrolidine 1 2]] Methyl] benzamide
(工程 1) (2S, 4S)— 4 フルオロー 2—(ヒドロキシメチル）ピロリジン 1 カルボ ン酸 tert ブチノレ エステノレ  (Step 1) (2S, 4S) — 4 Fluoro-2- (hydroxymethyl) pyrrolidine 1 Carbonic acid tert Butinole Estenole
[0302] [化 95]  [0302] [Chemical 95]
Figure imgf000106_0003
[0303] (2S, 4S) l—tert ブトキシカルボ二ルー 4 フルォロピロリジンー2 力ルボン 酸（2. 3g, lOmmol)及び THF (25ml)の溶液に BH .DMS (10M溶液、 3ml)を
Figure imgf000106_0003
[0303] (2S, 4S) l-tert-Butoxycarbonyl 4-fluoropyrrolidine-2 force Rubonic acid (2.3 g, lOmmol) and THF (25 ml) in a solution of BH .DMS (10 M solution, 3 ml)
3  Three
加え、室温で 1時間、さらに 60°Cで 2時間攪拌した。反応液に水を加え、酢酸ェチル で抽出した。抽出液を無水硫酸ナトリウムで乾燥、ろ過後、ろ液を減圧濃縮した。得ら れた残渣をフラッシュシリカゲルクロマトグラフィーに付し、へキサン：酢酸ェチル = 1： 1溶出部より得た分画を減圧濃縮し、標記化合物（2. 2g, 100%)を得た。  In addition, the mixture was stirred at room temperature for 1 hour and further at 60 ° C for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane: ethyl acetate = 1: 1 eluate was concentrated under reduced pressure to give the title compound (2.2 g, 100%).
NMR(CDC1 ) δ : 1. 48 (9Η, s) , 1. 95— 2. 37 (2Η, m) , 3. 48— 4. 27 (5Η,  NMR (CDC1) δ: 1. 48 (9Η, s), 1. 95— 2. 37 (2Η, m), 3. 48— 4. 27 (5Η,
3  Three
m) , 5. 09- 5. 22 (1Η, m) .  m), 5.09-5.22 (1mm, m).
(工程 2) (2S, 4S)— 4 フルオロー 2 [ [ (メタンスルホニル）ォキシ]メチル]ピロリ ジン 1一力ノレボン酸 tert ブチノレ エステノレ  (Step 2) (2S, 4S) — 4 Fluoro-2 [[((methanesulfonyl) oxy] methyl] pyrrolidine 1Strong Norebonic acid tert Butinole Estenole
[0304] [化 96] [0304] [Chemical 96]
F 。\ "... o  F. \ "... o
、Ν'  , Ν '
Boc  Boc
(2S, 4S)—4 フルオロー 2—(ヒドロキシメチノレ）ピロリジン 1一力ルボン酸 ter t ブチノレ エステル（2· 2g, lOmmol) , TEA(4. 2ml, 30mmol)及びジクロロメタ ン（50ml)の混合液に、 0°Cで塩化メタンスルホニル（1. 2ml, 15mmol)を加え、室 温で 4時間攪拌した。反応液に水を加え、ジクロロメタンで抽出した。抽出液を無水硫 酸ナトリウムで乾燥、ろ過後、ろ液を減圧濃縮した。得られた残渣を、フラッシュシリカ ゲルクロマトグラフィーに付し、へキサン：酢酸ェチル = 1： 1溶出部より得た分画を減 圧濃縮し、標記化合物（2. 5g, 84%)を得た。 (2S, 4S) -4 Fluoro-2- (hydroxymethinole) pyrrolidine 1 Mixture of rubonic acid ter t-butinole ester (2.2 g, lOmmol), TEA (4.2 ml, 30 mmol) and dichloromethane (50 ml) To the mixture was added methanesulfonyl chloride (1.2 ml, 15 mmol) at 0 ° C., and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel chromatography, and the fraction obtained from the eluate of hexane: ethyl acetate = 1: 1 was concentrated under reduced pressure to obtain the title compound (2.5 g, 84%). .
NMR(CDC1 ) δ : 1. 49 (9Η, s) , 2. 05— 2. 45 (2Η, m) , 3. 04 (3Η, s) , 3. 49  NMR (CDC1) δ: 1. 49 (9Η, s), 2. 05— 2. 45 (2Η, m), 3. 04 (3Η, s), 3. 49
3  Three
- 3. 75 (2Η, m) , 4. 06— 4. 22 (2Η, m) , 4. 49— 4. 52 (1Η, m) , 5. 18— 5. 31 (1Η, m)  -3.75 (2Η, m), 4. 06—4.22 (2Η, m), 4.49—4.52 (1Η, m), 5.18—5.31 (1Η, m)
(工程 3) (2S, 4S) - 2- (アジドメチル）ー4 フルォロピロリジン 1一力ルボン酸 tert ブチノレ エステノレ [0306] [化 97] (Step 3) (2S, 4S)-2- (azidomethyl) -4 fluoropyrrolidine 1 rugonic acid tert butynore Estenole [0306] [Chemical 97]
Figure imgf000108_0001
Figure imgf000108_0001
[0307] (2S, 4S)— 4 フルオロー 2 [[
Figure imgf000108_0002
[0307] (2S, 4S) — 4 fluoro-2 [[
Figure imgf000108_0002
一力ルボン酸 tert ブチノレ エステル（2.5g, 8.4mmol)及び DMF (30ml)の混 合液に、アジ化ナトリウム（2.73g, 42mmol)を加え、 70°Cでー晚攪拌した。反応液 を室温に冷却後、水を加え、酢酸ェチルで抽出した。抽出液を飽和食塩水で洗浄、 無水硫酸ナトリウムで乾燥、ろ過後、ろ液を減圧濃縮した。得られた残渣を、フラッシ ュシリカゲルクロマトグラフィーに付し、へキサン：酢酸ェチル =4: 1溶出部より得た分 画を減圧濃縮し、標記化合物（1.3g, 63%)を得た。  Sodium azide (2.73 g, 42 mmol) was added to a mixed solution of rubonic acid tert-butylol ester (2.5 g, 8.4 mmol) and DMF (30 ml), and the mixture was stirred at 70 ° C. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane: ethyl acetate = 4: 1 eluate was concentrated under reduced pressure to obtain the title compound (1.3 g, 63%).
NMR(CDC1 ) δ :1.48 (9Η, s) , 2.04— 2.35(2Η, m) , 3.18— 4.14 (5Η,  NMR (CDC1) δ: 1.48 (9Η, s), 2.04— 2.35 (2Η, m), 3.18— 4.14 (5Η,
3  Three
m), 5. 15-5.28(1Η, m) .  m), 5.15-5.28 (1Η, m).
(工程 4) (2S, 4S)— 2—(ァミノメチル）ー4 フルォロピロリジン 1一力ルボン酸 tert ブチノレ エステノレ  (Process 4) (2S, 4S) — 2- (Aminomethyl) -4 Fluoropyrrolidine 1 Monolithic rubonic acid tert Butinole Estenole
[0308] [化 98]  [0308] [Chemical 98]
Figure imgf000108_0003
Figure imgf000108_0003
(2S, 4S)— 2 （アジドメチル）ー4 フルォロピロリジン 1一力ルボン酸 tert— ブチル エステル（1· 3g, 5.3mmol)及びエタノール（50ml)の溶液に、 5%パラジ ゥム炭素（300mg)を加え、水素雰囲気下（1気圧）、室温で一晩攪拌した。触媒をろ 別後、ろ液を減圧濃縮して標記化合物（1.2g, 100%)を得た。 (2S, 4S) — 2 (azidomethyl) -4 fluoropyrrolidine 1 A solution of tert-butyl ester (1 · 3 g, 5.3 mmol) rubonic acid and ethanol (50 ml) in 5% palladium on carbon (300 mg ) And stirred overnight at room temperature under a hydrogen atmosphere (1 atm). After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to obtain the title compound (1.2 g, 100%).
MS (LC)m/z： 219(M" + H) .  MS (LC) m / z: 219 (M "+ H).
(工程 5) 4-[6-[ (tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダ ゾ [1, 2— b]ピリダジン一 3 ィル] 2 フルォロ一 N— [[(2S, 4S)-l-(tert- ブトキシカルボニル） 4 フルォロピ口リジン 2 ィル]メチノレ]ベンズアミド (Step 5) 4- [6-[(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-1-yl] 2-fluoro-N-[[(2S, 4S)- l- (tert- Butoxycarbonyl) 4 Fluoropilysine 2 yl] Methinole] benzamide
[化 99] [Chemical 99]
Figure imgf000109_0001
Figure imgf000109_0001
[実施例 14]に記載の 4 [6— [ (tert ブトキシカルボニル）（シクロプロピルメチル )ァミノ]イミダゾ [ 1 , 2 b]ピリダジン 3 ィル] 2 フルォロ安息香酸（213mg, 0. 5mmol)、 （2S, 4S)—2— (アミノメチル）一 4 フルォロピロリジン一 1 カルボン 酸 tert ブチノレ エステノレ（244mg, 1. Ommol)、 EDC (144mg, 0. 75mmol)、 HOBt(68mg, 0. 5mmol)、 TEA(278 1, 2. Ommol)及びジクロロメタン（15ml) の混合液を、室温で一晩攪拌した。反応混合液に水及び飽和炭酸水素ナトリウム水 溶液を加え、ジクロロメタンで抽出した。抽出液を無水硫酸ナトリウムで乾燥、ろ過後 、ろ液を減圧濃縮した。得られた残渣を分取 TLC (Merck, Silica— gel60, F , 1 4 [6 — [(tert-Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1,2b] pyridazine-3-yl] 2fluorobenzoic acid (213mg, 0.5mmol), described in [Example 14], 2S, 4S) -2- (Aminomethyl) 1-4 fluoropyrrolidine 1 1 carboxylic acid tert butynole Estenole (244 mg, 1. Ommol), EDC (144 mg, 0.775 mmol), HOBt (68 mg, 0.5 mmol), A mixture of TEA (278 1, 2. Ommol) and dichloromethane (15 ml) was stirred at room temperature overnight. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was separated by preparative TLC (Merck, Silica—gel60, F, 1
254 mm; 5%メタノール/ジクロロメタンで展開し、 30%メタノール/ジクロロメタンで溶出 )で精製し、標記化合物（230mg, 73%)を得た。  254 mm; developed with 5% methanol / dichloromethane and eluted with 30% methanol / dichloromethane) to give the title compound (230 mg, 73%).
NMR(CDC1 ) δ :0. 31— 0. 35(2H, m) , 0. 51— 0. 55(2H, m) , 1. 31— 1. 3  NMR (CDC1) δ: 0. 31— 0.35 (2H, m), 0.51 — 0.55 (2H, m), 1. 31— 1.3
3  Three
7(1H, m), 1.44-1. 59(18H, m) , 2. 16— 2. 34 (2H, m) , 3.49— 3. 81(4 H, m), 3. 88 (2H, d, J = 6. 86Hz), 4. 28— 4. 37(1H, m) , 5. 17— 5. 30(1 H, m), 7. 57-7. 61(1H, m) , 7. 89— 8. 15(5H, m) .  7 (1H, m), 1.44-1. 59 (18H, m), 2. 16— 2. 34 (2H, m), 3.49— 3. 81 (4 H, m), 3. 88 (2H, d , J = 6. 86Hz), 4. 28— 4. 37 (1H, m), 5. 17— 5. 30 (1 H, m), 7. 57-7. 61 (1H, m), 7. 89— 8. 15 (5H, m).
(工程 6) 4— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ーィル ]ー2 フルオロー N—[[(2S, 4S)— 4 フルォロピロリジンー2 ィル]メチ ノレ]ベンズアミド [0312] [化 100] (Step 6) 4- [6 -— [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] -2 Fluoro-N-[[(2S, 4S) -4 Fluoropyrrolidine-2 LE] METH NORE] benzamide [0312] [Chemical 100]
Figure imgf000110_0001
Figure imgf000110_0001
[0313] 4 [6— [(tert ブトキシカルボニル）（シクロプロピルメチル）ァミノ]イミダゾ [1, 2 —b]ピリダジンー3 ィル ]ー2 フルオロー N—[[(2S, 4S)—l—(tert ブトキシ カルボニル）ー4 フルォロピロリジンー2 ィル]メチノレ]ベンズアミド（230mg, 0.3 6mmol)、ジクロロメタン（10ml)及びトリフルォロ酢酸（10ml)の混合液を、室温で 2 時間攪拌した。反応混合物を減圧濃縮し、得られた濃縮残渣に飽和炭酸水素ナトリ ゥム水溶液を加えて中和後、ジクロロメタンで抽出した。抽出液を無水硫酸ナトリウム で乾燥、ろ過後、ろ液を減圧濃縮した。残渣を極少量のジクロロメタンに溶解し、酢酸 ェチルを少量加えて静置した後、析出した固形物をろ取、減圧乾燥して標記化合物 (120mg, 78%)を得た。 [0313] 4 [6— [(tert Butoxycarbonyl) (cyclopropylmethyl) amino] imidazo [1, 2 —b] pyridazine-3 yl] -2 Fluoro N — [[(2S, 4S) —l— (tert A mixture of butoxycarbonyl) -4 fluoropyrrolidine-2-yl] methinole] benzamide (230 mg, 0.3 6 mmol), dichloromethane (10 ml) and trifluoroacetic acid (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting concentrated residue was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a very small amount of dichloromethane, and a small amount of ethyl acetate was added and allowed to stand. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (120 mg, 78%).
NMR(CDC1 ) δ :0.33— 0.34 (2Η, m) , 0.61— 0.65(2Η, m) , 1.18— 1.2  NMR (CDC1) δ: 0.33— 0.34 (2 Η, m), 0.61— 0.65 (2 Η, m), 1.18— 1.2
3  Three
1(1Η, m), 1.85-1.94(1Η, m) , 2.21— 2.35(1Η, m) , 2.97— 3.11(1Η , m), 3.27-3.42 (3Η, m) , 3.51— 3.61 (4Η, m) , 3.75— 3.77(1Η, m) , 4.57-4.60(1Η, m) , 5. 15— 5.32(1Η, m) , 6.52(1Η, d, J = 9.52Hz) , 7 .70(1Η, d, J = 9.52Hz), 7.90— 7.96 (2Η, m) , 8.09— 8. 16(2Η, m) . IR(ATR)cm_1:3264, 2838, 1633, 1490. 1 (1Η, m), 1.85-1.94 (1Η, m), 2.21— 2.35 (1Η, m), 2.97— 3.11 (1Η, m), 3.27-3.42 (3Η, m), 3.51— 3.61 (4Η, m ), 3.75- 3.77 (1Η, m), 4.57-4.60 (1Η, m), 5. 15― 5.32 (1Η, m), 6.52 (1Η, d, J = 9.52Hz), 7.70 (1Η, d , J = 9.52Hz), 7.90— 7.96 (2 mm, m), 8.09— 8. 16 (2 mm, m) .IR (ATR) cm _1 : 3264, 2838, 1633, 1490.
MS (LC) m/z： 427 (M+ + H) . MS (LC) m / z: 427 (M + + H).
Anal. Calcd for C H F N O-0.5H 0:C, 60.68;H, 5.79;N, 19.30.  Anal.Calcd for C H F N O-0.5H 0: C, 60.68; H, 5.79; N, 19.30.
22 24 2 6 2  22 24 2 6 2
Found: C, 60.54;H, 5.60;N, 19.18.  Found: C, 60.54; H, 5.60; N, 19.18.
[実施例 19] [ (2R)— 2— (ピロリジン— 1—ィルメチル)ピロリジン— 1—ィル] = [4 -[6-[ (シクロブチル）ァミノ]イミダゾ [1 , 2-b]ピリダジン 3 ィル]フエニル] = ケトン [Example 19] [(2R) — 2- (Pyrrolidine-1-ylmethyl) pyrrolidine-1-yl] = [4- [6-[(cyclobutyl) amino] imidazo [1, 2-b] pyridazine 3 [Le] Phenyl] = Ketone
(工程 1) 3—ブロモー 6— [(シクロブチル）ァミノ]イミダゾ [1, 2— b]ピリダジン  (Step 1) 3-Bromo-6-[(Cyclobutyl) amino] imidazo [1, 2-b] pyridazine
[0314] [化 101] [0314] [Chem 101]
Figure imgf000111_0001
Figure imgf000111_0001
[0315] [参考例 1]に記載の 3—ブロモー 6—クロロイミダゾ [1, 2— b]ピリダジン（20· Og, 86. Ommol)、シクロブチノレアミン（14.8ml, 173mmol)、 TEA(48. Oml, 344m mol)及び N—メチルー 2—ピロリドン（80ml)の混合物を、封管中 120°Cで 17時間 攪拌した。反応液を室温に冷却後、減圧下にシクロブチルァミン及び TEAを留去し た。残留物にエーテルを加え、水及び飽和食塩水で洗浄後、エーテル層を分離した 。さらに水層をエーテルで抽出し、あわせたエーテル層を無水硫酸マグネシウムで乾 燥した。不溶物をろ過後、ろ液を減圧濃縮して標記化合物（21.9g, 95%)を得た。 NMR(DMSO-d ) δ :1.69— 1.79 (2Η, m) , 1.88— 1.98 (2Η, m) , 2.31 [0315] 3-Bromo-6-chloroimidazo [1, 2-b] pyridazine (20 · Og, 86. Ommol), cyclobutynoleamine (14.8 ml, 173 mmol), TEA (48 Oml, 344 mmol) and N-methyl-2-pyrrolidone (80 ml) were stirred in a sealed tube at 120 ° C for 17 hours. After cooling the reaction solution to room temperature, cyclobutylamine and TEA were distilled off under reduced pressure. Ether was added to the residue, and after washing with water and saturated brine, the ether layer was separated. Further, the aqueous layer was extracted with ether, and the combined ether layer was dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (21.9 g, 95%). NMR (DMSO-d) δ: 1.69— 1.79 (2Η, m), 1.88— 1.98 (2Η, m), 2.31
6  6
-2.40 (2Η, m), 4.17— 4.28(1Η, m) , 6.64(1Η, d, J = 9.6Hz) , 7.41(1 Η, d, J = 6.4Hz), 7.47(1Η, s) , 7.69(1Η, d, J = 9.6Hz) .  -2.40 (2Η, m), 4.17— 4.28 (1Η, m), 6.64 (1Η, d, J = 9.6Hz), 7.41 (1 Η, d, J = 6.4Hz), 7.47 (1Η, s), 7.69 (1Η, d, J = 9.6Hz).
MS (LC) m/z： 267(M+ + H) . MS (LC) m / z: 267 (M + + H).
(工程 2) 3—ブロモー 6—[(tert—ブトキシカルボニル）（シクロブチル）ァミノ]イミダ ゾ [1, 2— b]ピリダジン  (Step 2) 3-Bromo-6-[(tert-butoxycarbonyl) (cyclobutyl) amino] imidazo [1,2-b] pyridazine
[0316] [化 102] [0316] [Chemical 102]
Figure imgf000111_0002
[0317] 3 ブロモー 6 [(シクロブチル）ァミノ]イミダゾ [1, 2— b]ピリダジン（21· 9g, 82 . Ommol)、 Boc 0(36. Og, 165mmol) . TEA (46ml, 330mmol)、 DMAP(5.
Figure imgf000111_0002
[0317] 3 Bromo 6 [(cyclobutyl) amino] imidazo [1, 2-b] pyridazine (21 · 9 g, 82. Ommol), Boc 0 (36. Og, 165 mmol). TEA (46 ml, 330 mmol), DMAP ( Five.
2  2
Og, 40.9mmol)及び DMF(250ml)の混合液を、 60°Cで 2時間攪拌した。反応液 を室温に冷却後、減圧下で濃縮した。得られた濃縮残渣にエーテルを加え、水及び 飽和食塩水で洗浄後、エーテル層を分離した。エーテル層を無水硫酸マグネシウム で乾燥、ろ過後、ろ液を減圧濃縮した。得られた残留物をシリカゲルクロマトグラフィ 一に付し、ジクロロメタン:メタノール = 40:1溶出部より得た分画を減圧濃縮した。得 られた固形物をへキサン/酢酸ェチル混合液（30： 1)で洗浄して標記化合物（21. lg, 70%)を得た。  A mixture of Og, 40.9 mmol) and DMF (250 ml) was stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Ether was added to the obtained concentrated residue, and after washing with water and saturated brine, the ether layer was separated. The ether layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and the fraction obtained from the eluate of dichloromethane: methanol = 40: 1 was concentrated under reduced pressure. The obtained solid was washed with a hexane / ethyl acetate mixture (30: 1) to obtain the title compound (21. lg, 70%).
NMR(CDC1 ) δ :1.47(9H, s) , 1.62— 1.72 (2H, m) , 1.99— 2.11 (2H,  NMR (CDC1) δ: 1.47 (9H, s), 1.62— 1.72 (2H, m), 1.99— 2.11 (2H,
3  Three
m), 2.32-2.42 (2H, m) , 4.60— 4.71(1H, m) , 7.17(1H, d, J = 9.6Hz ), 7.73(1H, s), 7.83(1H, d, J = 9.6Hz) .  m), 2.32-2.42 (2H, m), 4.60— 4.71 (1H, m), 7.17 (1H, d, J = 9.6Hz), 7.73 (1H, s), 7.83 (1H, d, J = 9.6Hz ).
MS (LC) m/z： 367(M+ + H) . MS (LC) m / z: 367 (M + + H).
(工程 3) 4— [6— [(tert ブトキシカルボニル）（シクロブチル）ァミノ]イミダゾ [1, 2 b]ピリダジン 3—ィル]安息香酸  (Step 3) 4- [6 -— [(tert-Butoxycarbonyl) (cyclobutyl) amino] imidazo [1, 2 b] pyridazine 3-yl] benzoic acid
[0318] [化 103] [0318] [Chemical 103]
Boc  Boc
Figure imgf000112_0001
Figure imgf000112_0001
[0319] 3—ブロモー 6—[ (tert ブトキシカルボニル）（シクロブチル）ァミノ]イミダゾ [1, 2 —b]ピリダジン（3.00g, 8.17mmol)、 4— (4, 4, 5, 5 テトラメチノレ一 1, 3, 2— ジォキサボロラン 2 ィル）安息香酸（2· 03g, 8.17mmol)、リン酸三カリウム（水 禾ロ物）（6. 53g, 24. 5mmol)、 [PdCl (dppf) ]/ジクロロメタン錯体（1 : 1) (330mg [0319] 3-Bromo-6-[(tert-butoxycarbonyl) (cyclobutyl) amino] imidazo [1, 2 —b] pyridazine (3.00 g, 8.17 mmol), 4— (4, 4, 5, 5 tetramethylol 1, 3, 2-dioxaborolane 2 yl) benzoic acid (2 · 03g, 8.17mmol), tripotassium phosphate (water (6) (53 g, 24.5 mmol), [PdCl (dppf)] / dichloromethane complex (1: 1) (330 mg
2  2
, 0. 82mmol)及び水 /1, 4 ジォキサン混合液（3ml/27ml)の混合液を、アル ゴン気流中、加熱還流下に 14時間撹拌した。反応液に 4— (4, 4, 5, 5 テトラメチ ルー 1, 3, 2 ジォキサボロランー2 ィル）安息香酸（406mg, 1. 63mmol)を追 加し、さらに加熱還流下に 14時間撹拌した。反応液を室温に冷却後、酢酸ェチル（1 50ml)を加え、 20%リン酸三カリウム水溶液で抽出した。抽出液を酢酸ェチルで洗 浄後、クェン酸で中和し、生成した沈殿固形物を吸引ろ取した。得られた固形物を、 50°Cで減圧乾燥して標記化合物（2. 50g, 75%)を得た。  , 0.82 mmol) and a water / 1,4 dioxane mixture (3 ml / 27 ml) were stirred in an argon stream for 14 hours under heating and reflux. 4- (4, 4, 5, 5 tetramethyl 1, 3, 2 dioxaborolane-2-yl) benzoic acid (406 mg, 1.63 mmol) was added to the reaction mixture, and the mixture was further heated under reflux. Stir for hours. The reaction mixture was cooled to room temperature, ethyl acetate (150 ml) was added, and the mixture was extracted with 20% tripotassium phosphate aqueous solution. The extract was washed with ethyl acetate, neutralized with citrate, and the resulting precipitated solid was collected by suction filtration. The obtained solid was dried under reduced pressure at 50 ° C. to obtain the title compound (2.50 g, 75%).
NMR(DMSO-d ) δ :1.41 (9Η, s) , 1.49— 1. 67(2Η, m) , 2.01— 2. 13(  NMR (DMSO-d) δ: 1.41 (9Η, s), 1.49— 1.67 (2Η, m), 2.01— 2. 13 (
6  6
2Η, m), 2. 19-2. 28 (2Η, m) , 4. 60— 4. 69(1Η, m) , 7. 33(1Η, d, J = 9. 6Hz), 8.08 (2Η, d, J = 8. 6Hz) , 8. 22(1Η, d, J = 9. 6Hz) , 8. 29 (2Η, dt, J =8. 6, 2. ΟΗζ), 8.41(1Η, s) .  2Η, m), 2. 19-2. 28 (2Η, m), 4. 60— 4.69 (1Η, m), 7. 33 (1Η, d, J = 9.6Hz), 8.08 (2Η, d, J = 8.6Hz), 8.22 (1Η, d, J = 9.6Hz), 8.29 (2Η, dt, J = 8. 6, 2. ΟΗζ), 8.41 (1Η, s).
MS (LC) m/z： 409 (M+ + H) . MS (LC) m / z: 409 (M + + H).
(工程 4) [ (2R) -2- (ピロリジン一 1—ィルメチル）ピロリジン一 1—ィル] = [4- [6 [(シクロブチル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル]フエニル] =ケトン [化 104]  (Step 4) [(2R) -2- (Pyrrolidine 1-ylmethyl) pyrrolidine 1-yl] = [4- [6 [(Cyclobutyl) amino] imidazo [1, 2-b] pyridazine 3 yl] [Phenyl] = Ketone [Chemical 104]
Figure imgf000113_0001
Figure imgf000113_0001
4—[6—[(tert ブトキシカルボニル）（シクロブチル）ァミノ]イミダゾ [1, 2 b]ピリ ダジンー3 ィル]安息香酸（143mg, 0. 35mmol)、市販の（R)—(—）ー1ー（2— 合液に、 EDC(80. 9mg, 0.42mmol)、 HOBt (10. 8mg, 0.07mmol)及び TE A(0.10ml, 0.70mmol)を加え、室温で 60時間攪拌した。反応混合物に飽和炭 酸水素ナトリウム水溶液（20ml)を加えてしばらく攪拌後、クロ口ホルムで抽出した。 抽出液を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣を分取 TLC(M ERCK, Silica— gel60 F254, 1mm厚、ジクロロメタン：メタノール =9： 1)で精製 した。得られた油状物質のジクロロメタン（10ml)溶液に、トリフルォロ酢酸（5ml)を加 えて 3時間攪拌した。反応混合物を減圧濃縮し、濃縮残渣をジクロロメタン（10ml)に 溶解し、飽和炭酸水素ナトリウム水溶液（10ml)で洗浄した。ジクロロメタン層を無水 硫酸ナトリウムで乾燥後、減圧濃縮した。濃縮残渣にジクロロメタンとへキサンの混合 液を加え、固形物をろ取して標記化合物（lOOmg, 64%)を得た。 4- [6 -— ((tert-Butoxycarbonyl) (cyclobutyl) amino] imidazo [1, 2 b] pyridazine-3-yl] benzoic acid (143 mg, 0.35 mmol), commercially available (R) — (—)-1ー (2— EDC (80.9 mg, 0.42 mmol), HOBt (10.8 mg, 0.07 mmol) and TE A (0.10 ml, 0.70 mmol) was added and stirred at room temperature for 60 hours. A saturated aqueous sodium hydrogen carbonate solution (20 ml) was added to the reaction mixture, and the mixture was stirred for a while and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by preparative TLC (MERCK, Silica—gel 60 F254, 1 mm thickness, dichloromethane: methanol = 9: 1). To a solution of the obtained oily substance in dichloromethane (10 ml), trifluoroacetic acid (5 ml) was added and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was dissolved in dichloromethane (10 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (10 ml). The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A mixed solution of dichloromethane and hexane was added to the concentrated residue, and the solid was collected by filtration to obtain the title compound (lOOmg, 64%).
NMR(DMSO-d ) δ :1.24— 2.02(13H, m) , 2.17(2H, s) , 2.31— 2.42 NMR (DMSO-d) δ: 1.24— 2.02 (13H, m), 2.17 (2H, s), 2.31— 2.42
6  6
(3H, m), 2.56-2.72 (2H, m) , 2.98— 3.07(1H, m) , 3.51(1H, br s) , 3.69(1H, t, J = 6.9Hz), 4.18— 4.25(1H, m) , 6.68(1H, dd, J = 9.8, 2 .7Hz), 7.39(1H, t, J = 6.4Hz) , 7.58 (2H, d, J = 8.3Hz) , 7.77(1H, d, J =9.6Hz), 7.96(1H, d, J = 7.4Hz) , 8.25(2H, d, J = 8.6Hz) .  (3H, m), 2.56-2.72 (2H, m), 2.98—3.07 (1H, m), 3.51 (1H, br s), 3.69 (1H, t, J = 6.9Hz), 4.18— 4.25 (1H, m), 6.68 (1H, dd, J = 9.8, 2.7Hz), 7.39 (1H, t, J = 6.4Hz), 7.58 (2H, d, J = 8.3Hz), 7.77 (1H, d, J = 9.6Hz), 7.96 (1H, d, J = 7.4Hz), 8.25 (2H, d, J = 8.6Hz).
IR(ATR)cm_1:3264, 2964, 2786, 1606, 1573, 1477, 1294, 1168, 833, 810, 765. IR (ATR) cm _1 : 3264, 2964, 2786, 1606, 1573, 1477, 1294, 1168, 833, 810, 765.
MS (LC) m/z： 445 (M+ + H) . MS (LC) m / z: 445 (M + + H).
Anal. Calcd for C H N O-l.25H 0:C, 66.86;H, 7.44;N, 17.99. F  Anal.Calcd for C H N O-l.25H 0: C, 66.86; H, 7.44; N, 17.99. F
26 32 6 2  26 32 6 2
ound:C, 66.95;H, 7.41;N, 17.86. ound: C, 66.95; H, 7.41; N, 17.86.
[実施例 20] 4— [6 （シクロブチルァミノ）イミダゾ [1, 2— b]ピリダジン 3 ィル] 2—フルオロー N— [2—（ジメチルァミノ）ェチル]ベンズアミド 2塩酸塩  [Example 20] 4- [6 (Cyclobutylamino) imidazo [1,2-b] pyridazine 3-yl] 2-fluoro-N- [2- (dimethylamino) ethyl] benzamide dihydrochloride
(工程 1) 4 [6— [(tert ブトキシカルボニル）（シクロブチル）ァミノ]イミダゾ [1, 2 —b]ピリダジン 3 ィル ] 2 フルォロ安息香酸 (Step 1) 4 [6 — [(tert-Butoxycarbonyl) (cyclobutyl) amino] imidazo [1, 2 —b] pyridazine 3 yl] 2 Fluorobenzoic acid
[化 105] [Chemical 105]
Figure imgf000115_0001
Figure imgf000115_0001
[0323] [実施例 19]に記載の 3 ブロモー 6— [(tert ブトキシカルボニル）（シクロブチル )ァミノ]イミダゾ [1, 2— b]ピリダジン（8. Og, 21.8mmol)、 4 （ジヒドロキシボリル） —2 フルォロ安息香酸（5· 2g, 28.3mmol)、ジクロ口ビス（トリフエニルホスフィン） パラジウム（II) (800mg, 1.14mmol)及び 2M炭酸カリウム水溶液 /1, 4 ジォキ サン混合液（70ml/120ml)の混合液を、窒素気流下、 90°Cで 2時間撹拌した。反 応液を室温に冷却後、 4— (ジヒドロキシボリル）— 2 フルォロ安息香酸（1.2g, 6. 53mmol)を追加し、さらに窒素気流下、 90°Cで 3時間撹拌した。反応液を室温に冷 却後、 1, 4 ジォキサンを減圧下で留去した。残留物に水を加え、酢酸ェチルで洗 浄した。水層を、氷冷下で 2Mクェン酸を加えて中和し、生じた沈殿物を吸引ろ取し た。得られた固形物をジクロロメタン/メタノール混合液（20:1)に溶解し、無水硫酸 マグネシウムで乾燥、ろ過後、ろ液を減圧濃縮した。得られた固形物をエーテルで洗 浄し、標記化合物（7.61g, 82%)を得た。 [0323] 3 Bromo-6-[(tert-butoxycarbonyl) (cyclobutyl) amino] imidazo [1,2-b] pyridazine (8. Og, 21.8 mmol), 4 (dihydroxyboryl) described in [Example 19] — 2 Fluorobenzoic acid (5.2 g, 28.3 mmol), diclonal bis (triphenylphosphine) palladium (II) (800 mg, 1.14 mmol) and 2M aqueous potassium carbonate / 1,4 dioxane mixture (70 ml / 120 ml) The mixture was stirred at 90 ° C for 2 hours under a nitrogen stream. After the reaction solution was cooled to room temperature, 4- (dihydroxyboryl) -2-fluorobenzoic acid (1.2 g, 6.53 mmol) was added, and the mixture was further stirred at 90 ° C. for 3 hours under a nitrogen stream. After the reaction solution was cooled to room temperature, 1,4 dioxane was distilled off under reduced pressure. Water was added to the residue and washed with ethyl acetate. The aqueous layer was neutralized by adding 2M citrate under ice cooling, and the resulting precipitate was collected by suction filtration. The obtained solid was dissolved in a dichloromethane / methanol mixture (20: 1), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with ether to obtain the title compound (7.61 g, 82%).
NMR(DMSO-d ) δ :1.41 (9Η, s) , 1.53— 1.70 (2Η, m) , 2.03— 2.15(  NMR (DMSO-d) δ: 1.41 (9Η, s), 1.53— 1.70 (2Η, m), 2.03— 2.15 (
6  6
2Η, m), 2.20-2.29 (2Η, m) , 4.60— 4.70(1Η, m) , 7.37(1Η, d, J = 9. 6Hz), 8.01(1Η, t, J = 8.2Hz), 8.11(1Η, dd, J = 8.2, 1.5Hz) , 8.18(1 Η, dd, J=13.0, 1.5Hz), 8.25(1Η, d, J = 9.6Hz) , 8.51(1Η, s), 13.27 (1Η, br s).  2Η, m), 2.20-2.29 (2Η, m), 4.60- 4.70 (1Η, m), 7.37 (1Η, d, J = 9.6Hz), 8.01 (1Η, t, J = 8.2Hz), 8.11 ( 1Η, dd, J = 8.2, 1.5Hz), 8.18 (1Η, dd, J = 13.0, 1.5Hz), 8.25 (1Η, d, J = 9.6Hz), 8.51 (1Η, s), 13.27 (1Η, br s).
MS (LC) m/z： 427 (M+ + H) . MS (LC) m / z: 427 (M + + H).
(工程 2) 4— [6 （シクロブチルァミノ）イミダゾ [1, 2— b]ピリダジン 3 ィル] 2 フルオロー N— [2—（ジメチルァミノ）ェチル]ベンズアミド 2塩酸塩  (Step 2) 4- [6 (Cyclobutylamino) imidazo [1,2-b] pyridazine 3-yl] 2 Fluoro-N— [2- (Dimethylamino) ethyl] benzamide dihydrochloride
[0324] [化 106] [0324] [Chem 106]
Figure imgf000116_0001
4 [6— [(tert ブトキシカルボニル）（シクロブチル）ァミノ]イミダゾ [1, 2— b]ピリ ダジンー3 ィル ]ー2 フルォロ安息香酸（875mg, 2.05mmol)、N, N ジメチ ノレエチレンジァミン（0.543ml, 6.16mmol)及び DMF (20ml)の混合液に、 4一（ 4, 6 ジメトキシ一 1, 3, 5 トリァジン一 2 ィル） 4 メチルモルホリニゥム クロリ ド（821mg, 3.28mmol)を加え、室温で 18時間攪拌した。反応混合物を減圧濃縮 した。濃縮残渣を、フラッシュシリカゲルクロマトグラフィーに付し、ジクロロメタン:メタ ノール =10: 1溶出部より得た分画を減圧濃縮して油状物質を得た。得られた油状 物質に 4N塩酸（1, 4 ジォキサン溶液）（50ml)を加え、室温で 18時間攪拌した。 反応混合物を減圧濃縮し、得られた固形物を酢酸ェチルで洗浄して標記化合物（9 35mg, 83%)を得た。
Figure imgf000116_0001
4 [6 — [(tert-Butoxycarbonyl) (cyclobutyl) amino] imidazo [1,2-b] pyridazine-3 yl] -2 Fluorobenzoic acid (875 mg, 2.05 mmol), N, N dimethylenoethylenediamine (0.543 ml, 6.16 mmol) and DMF (20 ml) in a mixture of 4 (4, 6 dimethoxy-1,3,5 triazine-2-yl) 4 methylmorpholine chloride (821 mg, 3.28 mmol) And stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The concentrated residue was subjected to flash silica gel chromatography, and the fraction obtained from the eluate of dichloromethane: methanol = 10: 1 was concentrated under reduced pressure to obtain an oily substance. 4N Hydrochloric acid (1,4 dioxane solution) (50 ml) was added to the obtained oily substance, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was washed with ethyl acetate to obtain the title compound (935 mg, 83%).
NMR(CD OD) δ :1.84— 1.95(2H, m) , 2.04— 2.14(2H, m) , 2.45— 2.  NMR (CD OD) δ: 1.84— 1.95 (2H, m), 2.04— 2.14 (2H, m), 2.45— 2.
3  Three
53 (2H, m), 3.01 (6H, s) , 3.43 (2H, t, J = 6.0Hz) , 3.83(2H, t, J = 6.0 Hz), 4.26-4.34(1H, m) , 7.25(1H, d, J = 9.8Hz) , 7.99(1H, d, J = 9. 8Hz), 8.06-8.04 (2H, m) , 8.25(1H, d, J=13.0Hz) , 8.41(1H, s) . IR(ATR)cm_1:3212, 3041, 2636, 1698, 1656, 1500, 1400, 827, 773. MS (LC) m/z： 397 (M+ + H) . 53 (2H, m), 3.01 (6H, s), 3.43 (2H, t, J = 6.0Hz), 3.83 (2H, t, J = 6.0 Hz), 4.26-4.34 (1H, m), 7.25 (1H , d, J = 9.8Hz), 7.99 (1H, d, J = 9.8Hz), 8.06-8.04 (2H, m), 8.25 (1H, d, J = 13.0Hz), 8.41 (1H, s). IR (ATR) cm _1: 3212 , 3041, 2636, 1698, 1656, 1500, 1400, 827, 773. MS (LC) m / z: 397 (M + + H).
Anal. Calcd for C H FN 0-2HC1-4.25H 0:C, 46.20;H, 6.55;C1, 1  Anal.Calcd for C H FN 0-2HC1-4.25H 0: C, 46.20; H, 6.55; C1, 1
21 25 6 2  21 25 6 2
2.99;N, 15.39. Found :C, 45.88;H, 6.19;C1, 12.97;N, 15.76.  2.99; N, 15.39.Found: C, 45.88; H, 6.19; C1, 12.97; N, 15.76.
[実施例 21] 4— [6— (シクロブチルァミノ)イミダゾ [1, 2— b]ピリダジン— 3 ィル] 2 フルォロ N— [2—（ジェチルァミノ）ェチル]ベンズアミド [Example 21] 4— [6— (Cyclobutylamino) imidazo [1,2-b] pyridazine-3 yl] 2 Fluoro N— [2- (Jetylamino) ethyl] benzamide
Figure imgf000117_0001
Figure imgf000117_0001
[実施例 20]に記載の 4 [6— [ (tert ブトキシカルボニル）（シクロブチル）ァミノ] イミダゾ、 [1, 2 b]ピリダジン 3 ィノレ 2 フノレ才口安息、香酸（1· 28g, 3.00m mol)、N, N ジェチルエチレンジァミン（1.26ml, 9. OOmmol)及び DMF (30ml )の混合液に、 4— (4, 6 ジメトキシ— 1, 3, 5 トリァジン— 2 ィル）—4 メチル モノレホリニゥム クロリド（1.21g, 4.80mmol)¾OTEA(2.09ml, 15. Ommol) を加え、室温で 18時間攪拌した。反応混合物を減圧濃縮した。濃縮残渣をフラッシ ュシリカゲルクロマトグラフィーに付し、ジクロロメタン:メタノール =10:1溶出部より得 た分画を減圧濃縮して油状物質を得た。得られた油状物質に 4N塩酸（1, 4ージォ キサン溶液）（50ml)を加え、室温で 18時間攪拌した。反応混合物を減圧濃縮して 得られた固形物を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、 移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。得られた残 渣に飽和炭酸水素ナトリウム水溶液（50ml)を加え、ジクロロメタンにより抽出した。抽 出液を無水硫酸ナトリウムで乾燥した後、減圧濃縮して標記化合物（749mg, 57%) を得た。 4 [6 — [(tert-Butoxycarbonyl) (cyclobutyl) amino] imidazo, [1, 2 b] pyridazine 3 inore 2 funole, oral benzoate, fragrance (1.28 g, 3.00 mmol) described in [Example 20] ), N, N Jetylethylenediamine (1.26 ml, 9. OOmmol) and DMF (30 ml) in a mixed solution of 4— (4,6 dimethoxy-1,3,5 triazine—2 yl) —4 Methyl monorephorinum chloride (1.21 g, 4.80 mmol) ¾OTEA (2.09 ml, 15. Ommol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The concentrated residue was subjected to flash silica gel chromatography, and the fraction obtained from the eluate of dichloromethane: methanol = 10: 1 was concentrated under reduced pressure to obtain an oily substance. 4N Hydrochloric acid (1,4-dioxane solution) (50 ml) was added to the obtained oily substance, and the mixture was stirred at room temperature for 18 hours. The solid obtained by concentrating the reaction mixture under reduced pressure was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the resulting residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (749 mg, 57%).
NMR(DMSO-d ) δ :1.02(6H, br s) , 1.77— 1.88 (2H, m) , 1.95— 2.0  NMR (DMSO-d) δ: 1.02 (6H, br s), 1.77— 1.88 (2H, m), 1.95— 2.0
6  6
6(2H, m), 2.39-2.46 (2H, m) , 2.53— 2.76 (5H, br m) , 3.36— 3.47 (3H, m), 4.16-4.26(1H, m) , 6.73(1H, d, J = 9.8Hz) , 7.49(1H, d, J =5.9Hz), 7.78(1H, t, J = 8.1Hz), 7.80(1H, d, J = 9.8Hz) , 8.09(1H, dd, J = 8.1, 1.5Hz), 8.09(1H, s) , 8.13— 8.23(1H, br m) , 8.33(1H, d, J=13.5Hz). 6 (2H, m), 2.39-2.46 (2H, m), 2.53— 2.76 (5H, br m), 3.36— 3.47 (3H, m), 4.16-4.26 (1H, m), 6.73 (1H, d, J = 9.8Hz), 7.49 (1H, d, J = 5.9Hz), 7.78 (1H, t, J = 8.1Hz), 7.80 (1H, d, J = 9.8Hz), 8.09 (1H, dd, J = 8.1, 1.5Hz), 8.09 (1H, s), 8.13— 8.23 (1H, br m), 8.33 (1H, d, J = 13.5Hz).
IR(ATR)cm_1:3218, 3054, 2977, 2651, 1654, 1621, 1606, 1500, 1( , 827. IR (ATR) cm _1 : 3218, 3054, 2977, 2651, 1654, 1621, 1606, 1500, 1 (, 827.
MS (LC) m/z： 425 (M+ + H) . MS (LC) m / z: 425 (M + + H).
Anal. Calcd for C H FN O-0.75H 0:C, 63.07;H, 7.02;F, 4.34  Anal.Calcd for C H FN O-0.75H 0: C, 63.07; H, 7.02; F, 4.34
23 29 6 2  23 29 6 2
, 19.19. Found :C, 63.24;H, 6.77;F, 4.31;N, 18.98.  , 19.19.Found: C, 63.24; H, 6.77; F, 4.31; N, 18.98.
[実施例 22] 4— [6 [(シクロプチル)ァミノ]イミダゾ [1, 2— b]ピリダジン 3- ノレ] - 2—フルォロ N— [2—ピロリジン 1—ィルェチノレ]ベンズアミド  [Example 22] 4- [6 [(Cycloptyl) amino] imidazo [1,2-b] pyridazine 3-nore] -2-fluoro N- [2-pyrrolidine 1-ilcetinole] benzamide
[化 108][Chemical 108]
Figure imgf000118_0001
Figure imgf000118_0001
[実施例 20]に記載の 4 [6— [ (tert ブトキシカルボニル）（シクロブチル）ァミノ] イミダゾ、 [1, 2 b]ピリダジン 3 ィノレ] 2 フノレ才口安息、香酸（1· 29g, 3.00m mol)、 2 ピロリジン— 1—ィルェチルァミン（1.14ml, 9. OOmmol)及び DMF (30 ml)の混合液に、 4— (4, 6 ジメトキシ— 1, 3, 5 トリァジン— 2 ィル）—4 メチ ノレモノレホリュウム クロリド（1.21g, 4.80mmol)¾OTEA(2.09ml, 15. Ommol )を加え、室温で 18時間攪拌した。反応混合物を減圧濃縮した。濃縮残渣をフラッシ ュシリカゲルクロマトグラフィーに付し、ジクロロメタン:メタノール =10:1溶出部より得 た分画を減圧濃縮して油状物質を得た。得られた油状物質に 4N塩酸（1, 4ージォ キサン溶液）（50ml)を加え、室温で 18時間攪拌した。反応混合物を減圧濃縮して 得られた固形物を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、 移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。得られた残 渣に飽和炭酸水素ナトリウム水溶液（50ml)を加え、ジクロロメタンで抽出した。抽出 液を無水硫酸ナトリウムで乾燥後、減圧濃縮して標記化合物（750mg, 57%)を得た 4 [6— [(tert-Butoxycarbonyl) (cyclobutyl) amino] imidazo, [1, 2 b] pyridazine 3 inore] described in [Example 20] 2 Funole-born mouth benzoate, perfume acid (1.29 g, 3.00 m mol), 2 pyrrolidine-1-ylethylamine (1.14 ml, 9. OOmmol) and DMF (30 ml) in a mixed solution of 4-(4, 6 dimethoxy-1, 3, 5 triazine-2 yl)-4 methyl Noremonorechlorium chloride (1.21 g, 4.80 mmol) ¾OTEA (2.09 ml, 15. Ommol) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure. The concentrated residue was subjected to flash silica gel chromatography, and the fraction obtained from the eluate of dichloromethane: methanol = 10: 1 was concentrated under reduced pressure to obtain an oily substance. 4N Hydrochloric acid (1,4-dioxane solution) (50 ml) was added to the obtained oily substance, and the mixture was stirred at room temperature for 18 hours. The solid obtained by concentrating the reaction mixture under reduced pressure was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. Obtained residue Saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (750 mg, 57%).
NMR(DMSO-d ) δ :1.66— 1.73 (4Η, m) , 1.77— 1.88 (2Η, m) , 1.94 NMR (DMSO-d) δ: 1.66— 1.73 (4Η, m), 1.77— 1.88 (2Η, m), 1.94
6  6
-2.06 (2Η, m), 2.39— 2.47 (3Η, m) , 2.59 (2H, t, J=7.4Hz) , 3.29— 3.31 (2H, m), 3.35— 3.44 (3H, m) , 4.21(1H, dt, J = 21.7, 7.6Hz) , 6 .72(1H, d, J = 9.6Hz), 7.48(1H, d, J = 6.1Hz), 7.74(1H, t, J = 8.1Hz ), 7.80(1H, d, J = 9.6Hz), 8.06(1H, d, J=l.7Hz) , 8.08(1H, s) , 8. 18 -8.22(1H, m), 8.31(1H, dd, J=13.2, 1.5Hz) .  -2.06 (2Η, m), 2.39— 2.47 (3Η, m), 2.59 (2H, t, J = 7.4Hz), 3.29— 3.31 (2H, m), 3.35— 3.44 (3H, m), 4.21 (1H , dt, J = 21.7, 7.6Hz), 6.72 (1H, d, J = 9.6Hz), 7.48 (1H, d, J = 6.1Hz), 7.74 (1H, t, J = 8.1Hz), 7.80 (1H, d, J = 9.6Hz), 8.06 (1H, d, J = l.7Hz), 8.08 (1H, s), 8. 18 -8.22 (1H, m), 8.31 (1H, dd, J = 13.2, 1.5Hz).
MS (LC) m/z： 423 (M+ + H) . MS (LC) m / z: 423 (M + + H).
Anal. Calcd for C H FN O-0.75H 0:C, 63.36;H, 6.59;F, 4.36;N  Anal.Calcd for C H FN O-0.75H 0: C, 63.36; H, 6.59; F, 4.36; N
23 27 6 2  23 27 6 2
, 19.27. Found :C, 63.37, H, 6.45;F, 4.29;N, 19.08.  , 19.27.Found: C, 63.37, H, 6.45; F, 4.29; N, 19.08.
[実施例 23] 4— [6 [(シクロプロピルメチル)ァミノ]イミダゾ [1, 2— b]ピリダジン — 3 ィル] 2 フルォロ N— [(2S) ピロリジン— 2 ィルメチル]ベンズアミド 2塩酸塩  [Example 23] 4— [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine—3 yl] 2 Fluoro N — [(2S) pyrrolidine-2-ylmethyl] benzamide dihydrochloride
(工程 1) 4— [6— [(シクロプロピルメチル)ァミノ]イミダゾ ， 2— b]ピリダジン—3 ーィル ] 2—フルォロベンズアルデヒド (Step 1) 4 - [6 - [(cyclopropylmethyl) Amino] imidazo, 2 - b] pyridazine - 3 Iru] 2 Full O b benzaldehyde
[0330] [化 109] [0330] [Chem 109]
Figure imgf000119_0001
Figure imgf000119_0001
[0331] [実施例 2]に記載の 3 ブロモー 6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2 — b]ピリダジン（200mg, 0.75mmol)、 3 フルオロー 4 ホルミルフエニルボロン 酸（190mg, 1. lmmol)、 [PdCl (dppf) ]/ジクロロメタン錯体（1 : 1) (33mg, 0. 0 [0331] 3 Bromo-6 [(cyclopropylmethyl) amino] imidazo [1, 2 — b] pyridazine (200 mg, 0.75 mmol), 3 Fluoro-4 formylphenylboron described in [Example 2] Acid (190mg, 1.lmmol), [PdCl (dppf)] / dichloromethane complex (1: 1) (33mg, 0.0.0
2  2
4mmol)、リン酸三カリウム（水和物）（600mg)及び 1 , 4 ジォキサン（20ml)の混 合液を、アルゴン雰囲気下、 80°Cで 18時間撹拌した。反応液を室温に冷却後、酢 酸ェチルを加え、不溶物をセライトを用いたろ過で除去した。ろ液を減圧濃縮し、残 留物を分取 TLC (Merck, Silica— gel60, F , 1mm ; 5%メタノール/ジクロロメタ  4 mmol), tripotassium phosphate (hydrate) (600 mg) and 1,4 dioxane (20 ml) were stirred at 80 ° C. for 18 hours under an argon atmosphere. The reaction solution was cooled to room temperature, ethyl acetate was added, and insolubles were removed by filtration using celite. The filtrate was concentrated under reduced pressure, and the residue was collected by TLC (Merck, Silica-gel60, F, 1 mm; 5% methanol / dichlorometa
254  254
ンで展開し、 30%メタノール/ジクロロメタンで溶出）で精製し、標記化合物（90mg, 39%)を得た。  And eluted with 30% methanol / dichloromethane) to give the title compound (90 mg, 39%).
MS (LC) m/z : 311 (M+ + H) .  MS (LC) m / z: 311 (M + + H).
(工程 2) 4— [6 [ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジンー3 ィル] 2—フルォロ安息香酸  (Step 2) 4- [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3yl] 2-Fluorobenzoic acid
[0332] [化 110] [0332] [Chem 110]
Figure imgf000120_0001
Figure imgf000120_0001
[0333] 4 [6 [ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィル] [0333] 4 [6 [(Cyclopropylmethyl) amino] imidazo [1, 2-b] pyridazine 3 yl]
2 フルォロベンズアルデヒド（lOOmg, 0. 32mmol)、 2 メチル 2 ブテン（0. 1 70ml, 1. 6mmol)、リン酸二水素ナトリウム二水和物（75mg, 0. 48mmol)及び ter t ブチルアルコール/水/メタノール混合液（4 : 1 : 4, 9ml)の懸濁液に、亜塩素 酸ナトリウム（80%) (144mg, 1. 28mmol)を加え、室温で 5時間攪拌した。反応液 に 1N塩酸を加え、ジクロロメタンで抽出した。さらに、水層を 1N水酸化ナトリウム水溶 液で中和後、ジクロロメタン/メタノール混合液で再抽出した。合わせた抽出液を無 水硫酸ナトリウムで乾燥し、減圧濃縮した。濃縮残渣を分取 TLC (Merck, Silica— gel60, F , 1mm ; 18%メタノール/ジクロロメタンで展開し、クロ口ホルム/メタノ  2 Fluorobenzaldehyde (lOOmg, 0.32 mmol), 2 Methyl 2-butene (0.1 70 ml, 1.6 mmol), Sodium dihydrogen phosphate dihydrate (75 mg, 0.48 mmol) and tert-butyl alcohol / Sodium chlorite (80%) (144 mg, 1.28 mmol) was added to a suspension of a water / methanol mixture (4: 1: 4, 9 ml), and the mixture was stirred at room temperature for 5 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with dichloromethane. Further, the aqueous layer was neutralized with a 1N aqueous sodium hydroxide solution and then re-extracted with a dichloromethane / methanol mixture. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was separated with preparative TLC (Merck, Silica-gel60, F, 1 mm; developed with 18% methanol / dichloromethane,
254  254
ール/水/ = 7/3/1の下層で溶出）で精製し、標記化合物（320mg, 100%)を 得た。 Eluate in the lower layer of water / water / = 7/3/1) to give the title compound (320 mg, 100%) Obtained.
MS (LC) m/z： 327 (M+ + H) . MS (LC) m / z: 327 (M + + H).
(工程 3) 4— [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ーィル ] 2—フルオロー N— [ (2S) 1一（tert ブトキシカルボ二ノレ）ピロリジン 2 ィルメチル]ベンズアミド  (Step 3) 4- [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3-yl] 2-fluoro-N- [(2S) 1-((tert-butoxycarboninole) pyrrolidine 2-ylmethyl] Benzamide
[化 111] [Chem 111]
Figure imgf000121_0001
Figure imgf000121_0001
2 フルォロ安息香酸（105mg, 0. 32mmol)、市販の（2S)— 2 （アミノメチル）ピ 口リジン一 1—カルボン酸 tert ブチノレ エステノレ（128mg, 0. 64mmol)、EDC( 92mg, 0.48mmol)、 HOBt(45mg, 0. 32mmol)、 TEA(0. 177ml, 1. 28mm ol)及びジクロロメタン/ THF混合液（5ml/8ml)の混合液を、室温でー晚攪拌した 。反応混合液に水及び飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出 した。抽出液を無水硫酸ナトリウムで乾燥、ろ過後、ろ液を減圧濃縮した。得られた残 渣を分取 TLC (Merck, Silica— gel60, F , 1mm; 8%メタノール 7ジクロロメタン 2 Fluorobenzoic acid (105 mg, 0.32 mmol), commercially available (2S) -2 (aminomethyl) pi-lysine mono 1-carboxylic acid tert butynole Estenole (128 mg, 0.64 mmol), EDC (92 mg, 0.48 mmol), A mixture of HOBt (45 mg, 0.32 mmol), TEA (0.177 ml, 1.28 mmol) and a dichloromethane / THF mixture (5 ml / 8 ml) was stirred at room temperature. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was collected by TLC (Merck, Silica-gel60, F, 1 mm; 8% methanol 7 dichloromethane
254  254
で展開し、 30%メタノール/ジクロロメタンで溶出）で精製し、標記化合物（34mg, 2 1%)を得た。 And eluted with 30% methanol / dichloromethane) to give the title compound (34 mg, 21%).
NMR(CDC1 ) δ :0. 32— 0. 34 (2Η, m) , 0. 60— 0. 62(2Η, m) , 1. 12— 2.0  NMR (CDC1) δ: 0. 32— 0.34 (2 m, m), 0.60— 0.62 (2 Η, m), 1. 12— 2.0
3  Three
7(14Η, m), 3. 24— 3. 74 (7Η, m) , 4. 13— 4. 15(1Η, m) , 4. 55— 4. 57(1 Η, m), 6. 51-6. 53(1Η, m) , 7. 69— 7. 71(1Η, m) , 7. 89— 8. 15(4Η, m (工程 4) 4 [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 —ィル ]— 2—フルォ口 N— [(2S)—ピロリジン— 2—ィルメチル]ベンズアミド 2塩 酸塩 7 (14 mm, m), 3.24— 3.74 (7 mm, m), 4.13— 4. 15 (1 mm, m), 4.55—4.57 (1 mm, m), 6. 51 -6. 53 (1Η, m), 7. 69— 7.71 (1Η, m), 7. 89— 8. 15 (4Η, m (Step 4) 4 [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine-3 —yl] — 2-Fluoro-N — [(2S) -Pyrrolidine-2-ylmethyl] benzamide 2 salt Acid salt
[0336] [化 112] [0336] [Chem 112]
Figure imgf000122_0001
Figure imgf000122_0001
[0337] 4 [6 [ (シクロプロピルメチル）ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィル] 2—フルオロー N— [ (2S) 1— (tert ブトキシカルボ二ノレ）ピロリジン一 2—ィルメ チル]ベンズアミド（34mg, 0.066mmol)及び 4N塩酸（1, 4 ジォキサン溶液）（1 5ml)の混合液を、室温で 2.5時間攪拌した。反応液を減圧濃縮し、少量のジェチ ルエーテルを加えて静置した。析出した固形物をろ取して標記化合物（24mg, 88 %)を得た。 [0337] 4 [6 [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3 yl] 2-fluoro-N— [(2S) 1— (tert-butoxycarboninole) pyrrolidine 1-ilme A mixture of til] benzamide (34 mg, 0.066 mmol) and 4N hydrochloric acid (1,4 dioxane solution) (15 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, a small amount of diethyl ether was added, and the mixture was allowed to stand. The precipitated solid was collected by filtration to obtain the title compound (24 mg, 88%).
NMR(DMSO-d ) δ :0.28— 0.30 (2Η, m) , 0.52— 0.54 (2Η, m) , 1.18  NMR (DMSO-d) δ: 0.28— 0.30 (2Η, m), 0.52— 0.54 (2Η, m), 1.18
6  6
-1.20(1Η, m), 1.62-2. 10 (4Η, m) , 3.14— 3.72(7Η, m) , 7.09— 7. 12(1Η, m), 7.75(1Η, br s) , 7.88(1Η, t, J = 8.06Hz) , 7.96(1Η, d, J = 9.52Hz), 8.11(1Η, dd, J = 8.18, 1.59Hz), 8.26(1Η, d, J=12.70Hz) , 8.41(1Η, br s) , 8.66(1Η, br s) , 9.22(1Η, br s) .  -1.20 (1Η, m), 1.62-2. 10 (4Η, m), 3.14—3.72 (7Η, m), 7.09—7.12 (1Η, m), 7.75 (1Η, br s), 7.88 (1Η , t, J = 8.06Hz), 7.96 (1Η, d, J = 9.52Hz), 8.11 (1Η, dd, J = 8.18, 1.59Hz), 8.26 (1Η, d, J = 12.70Hz), 8.41 (1Η , br s), 8.66 (1Η, br s), 9.22 (1 (, br s).
MS (LC) m/z： 409 (M+ + H) . MS (LC) m / z: 409 (M + + H).
[実施例 24] 4— [6— [(3—クロ口ベンジル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル] N— [2—（ジメチルァミノ）ェチル]ベンズアミド ギ酸塩  [Example 24] 4— [6 — [(3-Clorobenzyl) amino] imidazo [1,2-b] pyridazine-3-yl] N— [2- (dimethylamino) ethyl] benzamide formate
(工程 1) クロロイミダゾ ， 2 b]ピリダジン ィル)安息香酸 ェチル エステノレ (Step 1) chloroimidazo, 2 b] pyridazine I le) benzoate Echiru Esutenore
Figure imgf000123_0001
Figure imgf000123_0001
[0339] [参考例 1 ]に記載の 3 ブロモ 6 クロロイミダゾ [ 1 , 2— b]ピリダジン（800mg, 3. 44mmol)、 4 エトキシカルボユルフェニルボロン酸（1. 33g, 6. 86mmol)、 [P dCl (dppf) ]/ジクロロメタン錯体（1 : 1) (280mg, 0. 343mmol)、 dppf (192mg,[0339] 3 Bromo 6 chloroimidazo [1,2-b] pyridazine (800 mg, 3.44 mmol), 4 ethoxycarboylphenylboronic acid (1.33 g, 6.86 mmol) described in [Reference Example 1], P dCl (dppf)] / dichloromethane complex (1: 1) (280 mg, 0.343 mmol), dppf (192 mg,
2 2
0. 346mmol)、リン酸三カリウム（水和物）（4· 60g)及び 1 , 4 ジォキサン（20ml) の混合液を、窒素気流下、 90— 95°Cで 6時間撹拌した。反応液を室温に冷却後、 酢酸ェチルを加え、不溶物をセライトを用いてろ過で除去した。ろ液を減圧濃縮し、 得られた残留物をフラッシュシリカゲルクロマトグラフィーに付し、へキサン:酢酸ェチ ル= 1： 2溶出部より得た分画を減圧濃縮して標記化合物（294mg, 28%)を得た。 NMR(CDC1 ) δ : 1. 43 (3Η, t, J = 7. 3Hz) , 4. 41 (2H, q, J= 7. 3Hz) , 7. 14  0.346 mmol), tripotassium phosphate (hydrate) (4 · 60 g) and 1,4 dioxane (20 ml) were stirred at 90-95 ° C. for 6 hours under a nitrogen stream. The reaction solution was cooled to room temperature, ethyl acetate was added, and insoluble materials were removed by filtration using Celite. The filtrate was concentrated under reduced pressure, the obtained residue was subjected to flash silica gel chromatography, and the fraction obtained from the hexane: ethyl acetate = 1: 2 eluate was concentrated under reduced pressure to give the title compound (294 mg, 28 %). NMR (CDC1) δ: 1.43 (3Η, t, J = 7.3Hz), 4.41 (2H, q, J = 7.3Hz), 7.14
3  Three
(1H, d, J = 9. 2Hz) , 7. 99 (1H, d, J = 9. 2Hz) , 8. 13— 8. 21 (5H, m) . MS (LC) m/z： 302 (M+ + H) . (1H, d, J = 9.2Hz), 7.99 (1H, d, J = 9.2Hz), 8. 13—8.21 (5H, m). MS (LC) m / z: 302 ( M ++ H).
(工程 2) 4— (6 クロロイミダゾ [1 , 2— b]ピリダジンー3 ィル） N—[2 （ジメ チルァミノ）ェチル]ベンズアミド ギ酸塩  (Step 2) 4— (6 Chloroimidazo [1, 2— b] pyridazine-3-yl) N— [2 (dimethylamino) ethyl] benzamide formate
[0340] [化 114] [0340] [Chemical 114]
Figure imgf000123_0002
[0341] 4—（6 クロロイミダゾ [1 , 2 b]ピリダジン 3 ィル）安息香酸 ェチル エステ ノレ（280mg, 0. 928mmol)、メタノーノレ（60ml)及び IN水酸ィ匕ナトリウム水溶 ί夜（5 . Oml)の混合液を、加熱還流下に 40分間攪拌した。反応液を室温に冷却後、減圧 濃縮した。濃縮残渣に水及び 1N塩酸を加えて pH4とした。生成した沈殿物を減圧ろ 取した後、ろ液を減圧乾燥して固形物（197mg)を得た。得られた固形物、 N, N— ジメチノレエチレンジァミン（0. 095ml, 0. 865mmol)、 TEA(0. 195ml, 1. 40mm ol)及び DMF (lOml)の混合液に、 BOP (380mg, 0. 859mmol)をカロえ、室温で 4 時間攪拌した後、反応混合物を減圧濃縮した。濃縮残渣に水を加え、生じた沈殿物 をろ取した。得られた沈殿物を分取 HPLC (カラム： NOMURA Develosil Combi RP— 5、移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。 得られた固形物をエーテルで洗浄して標記化合物（104mg, 28%)を得た。
Figure imgf000123_0002
[0341] 4— (6 Chloroimidazo [1, 2 b] pyridazine 3 yl) Ethyl ester benzoate (280 mg, 0.928 mmol), methanol (60 ml) and IN aqueous sodium hydroxide aqueous solution (5. Oml) was stirred for 40 minutes under heating to reflux. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water and 1N hydrochloric acid were added to the concentrated residue to adjust the pH to 4. The produced precipitate was collected by filtration under reduced pressure, and the filtrate was dried under reduced pressure to obtain a solid (197 mg). The resulting solid, N, N-dimethylenoethylenediamine (0.095 ml, 0.865 mmol), TEA (0.195 ml, 1.40 mmol) and DMF (10 ml) were mixed with BOP (380 mg , 0.859 mmol), and after stirring at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure. Water was added to the concentrated residue, and the resulting precipitate was collected by filtration. The resulting precipitate was purified by preparative HPLC (column: NOMURA Develosil Combi RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. The obtained solid was washed with ether to obtain the title compound (104 mg, 28%).
NMR(DMSO-d ) δ : 2. 87 (3H, s) , 2. 88 (3H, s) , 3. 29 (2H, q, J = 5. 9H  NMR (DMSO-d) δ: 2.87 (3H, s), 2.88 (3H, s), 3.29 (2H, q, J = 5.9H
6  6
z) , 3. 64 (2H, q, J = 5. 9Hz) , 7. 49 (1H, d, J = 9. 5Hz) , 8. 02 (2H, d, J = 8 . 5Hz) , 8. 26 (2H, d, J = 8. 5Hz) , 8. 35 (1H, d, J = 9. 5Hz) , 8. 45 (1H, s) , 8. 76 (1H, t, J = 5. 6Hz) .  z), 3.64 (2H, q, J = 5.9Hz), 7.49 (1H, d, J = 9.5Hz), 8.02 (2H, d, J = 8.5Hz), 8. 26 (2H, d, J = 8.5 Hz), 8. 35 (1H, d, J = 9.5 Hz), 8. 45 (1H, s), 8. 76 (1H, t, J = 5.6 Hz ).
MS (LC) m/z： 344 (M+ + H) . MS (LC) m / z: 344 (M + + H).
(工程 3) 4— [6— [ (3—クロ口ベンジル）ァミノ]イミダゾ [1 , 2— b]ピリダジンー3— ィル] N— [2—（ジメチルァミノ）ェチル]ベンズアミド ギ酸塩  (Step 3) 4— [6— [(3-Clorobenzyl) amino] imidazo [1, 2-b] pyridazine-3-yl] N— [2- (dimethylamino) ethyl] benzamide formate
[0342] [化 115] [0342] [Chemical 115]
Figure imgf000124_0001
Figure imgf000124_0001
[0343] 4—（6 クロロイミダゾ [1 , 2— b]ピリダジンー3 ィル） N— [2 （ジメチルァミノ )ェチル]ベンズアミド ギ酸塩（50mg, 0. 128mmol)、 DMSO (0. 4ml)及び 3 ク ロロべンジノレアミン（0. 0627ml, 0. 513mmol)の混合 ί夜を、 125。Cで 2日寺間、さら に 140°Cで 2時間攪拌した。反応液を室温に冷却後、減圧濃縮した。濃縮残渣に D MF (6ml)を加え、 PS— Isocyanate (ARGONAUT TECHNOLOGIES Inc. ) (1. 07g, 1. 44mmol/g)を加えて 13時間攪拌した。反応混合液をろ過後、ろ液 を減圧濃縮した。得られた残渣を分取 HPLC (カラム： NOMURA Develosil Co mbi— RP— 5、移動相：ァセトニトリル/水/ギ酸)で精製し、得られた分画を減圧濃 縮して標記化合物（2. 60mg, 4. 1 %)を得た。 [0343] 4— (6 Chloroimidazo [1, 2— b] pyridazine-3 yl) N— [2 (Dimethylamino) ) Ethyl] benzamide formate (50 mg, 0.128 mmol), DMSO (0.4 ml) and 3 chlorobenenoamine (0.0627 ml, 0.513 mmol). The mixture was stirred for 2 days at C and 2 hours at 140 ° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. DMF (6 ml) was added to the concentrated residue, PS—Isocyanate (ARGONAUT TECHNOLOGIES Inc.) (1.07 g, 1.44 mmol / g) was added, and the mixture was stirred for 13 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the obtained fraction was concentrated under reduced pressure to give the title compound (2. 60 mg , 4.1%).
MS (LC) m/z： 449 (M" + H) . MS (LC) m / z: 449 (M "+ H).
[実施例 25] 4— [6— [ (4ーメトキシベンジル)ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィル] N— [2 （ジメチルァミノ）ェチル]ベンズアミド ギ酸塩  [Example 25] 4- [6 -— [(4-Methoxybenzyl) amino] imidazo [1,2-b] pyridazine 3-yl] N— [2 (dimethylamino) ethyl] benzamide formate
[化 116] [Chem 116]
Figure imgf000125_0001
Figure imgf000125_0001
[実施例 24]に記載の 4一（6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル） N [2—(ジメチルァミノ）ェチル]ベンズアミド ギ酸塩（50mg, 0. 128mmol)、DM SO (0. 4ml)及び 4 メトキシべンジノレアミン（0. 0670ml, 0. 513mmol)の混合 ί夜 を、 125°Cで 2時間、さらに 140°Cで 2時間攪拌した。反応液を室温に冷却後、減圧 濃縮した。濃縮残渣に DMF (6ml)を加え、 PS— Isocyanate (ARGONAUT TE CHNOLOGIES Inc. ) (1. 07g, 1. 44mmol/g)を加えて 13時間攪拌した。反 応混合液をろ過後、ろ液を減圧濃縮した。得られた残渣を分取 HPLC (カラム： NO MURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し 、 目的分画を減圧濃縮して標記化合物（5.30mg, 8.4%)を得た。 [Example 24] 4- (6-chloroimidazo [1,2-b] pyridazine 3-yl) N [2- (dimethylamino) ethyl] benzamide formate (50 mg, 0.128 mmol), DM SO (0 4 ml) and 4 methoxybenzylinamine (0.0670 ml, 0.513 mmol) were stirred at 125 ° C. for 2 hours and further at 140 ° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. DMF (6 ml) was added to the concentrated residue, PS—Isocyanate (ARGONAUT TE CHNOLOGIES Inc.) (1.07 g, 1.44 mmol / g) was added, and the mixture was stirred for 13 hours. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: NO MURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid). The desired fraction was concentrated under reduced pressure to obtain the title compound (5.30 mg, 8.4%).
NMR(DMSO-d ) δ :2.23— 2.26 (6Η, m) , 2.51— 2.52 (2Η, m) , 3.36 NMR (DMSO-d) δ: 2.23— 2.26 (6 Η, m), 2.51— 2.52 (2 Η, m), 3.36
6  6
-3.42 (2Η, m), 3.71 (3Η, s) , 4.43 (2H, d, J = 5.4Hz) , 6.79(1H, d, J =9.7Hz), 6.92 (2H, dt, J = 8.8, 2.5Hz) , 7.35(2H, d, J = 8.8Hz) , 7.6 3(1H, t, J = 5.4Hz), 7.78(1H, d, J = 9.7Hz) , 7.87(2H, d, J = 8.5Hz) , 7.97(1H, s), 8.14-8.19(3H, m) , 8.43(1H, t, J = 5.4Hz) .  -3.42 (2Η, m), 3.71 (3Η, s), 4.43 (2H, d, J = 5.4Hz), 6.79 (1H, d, J = 9.7Hz), 6.92 (2H, dt, J = 8.8, 2.5 Hz), 7.35 (2H, d, J = 8.8Hz), 7.6 3 (1H, t, J = 5.4Hz), 7.78 (1H, d, J = 9.7Hz), 7.87 (2H, d, J = 8.5Hz) ), 7.97 (1H, s), 8.14-8.19 (3H, m), 8.43 (1H, t, J = 5.4Hz).
MS (LC) m/z： 445 (M+ + H) . MS (LC) m / z: 445 (M + + H).
[実施例 26] 4— [6—(ペンジノレアミノ)イミダゾ [1, 2— b]ピリダジンー3 ィル] [Example 26] 4- [6- (Pendinoreamino) imidazo [1,2-b] pyridazine-3 yl]
N-[(2S) ピロリジン 2—ィルメチル]ベンズアミド ギ酸塩 N-[(2S) pyrrolidine 2-ylmethyl] benzamide formate
(工程 1) クロロイミダゾ ， 2 b]ピリダジン ィル)安息香酸 メチル エステノレ (Step 1) chloroimidazo, 2 b] pyridazine I) methyl benzoate Esutenore
[化 117] [Chemical 117]
Figure imgf000126_0001
Figure imgf000126_0001
[参考例 1]に記載の 3—ブロモー 6—クロロイミダゾ [1, 2— b]ピリダジン（8· Og, 3 4.4mmol)、 4 メトキシカルボユルフェニルボロン酸（6.19g, 34.4mmol)、 [Pd CI (dppf)]/ジクロロメタン錯体（1:1) (1· 39g, 1.72mmol)、リン酸三カリウム（3-bromo-6-chloroimidazo [1, 2-b] pyridazine (8 · Og, 3 4.4 mmol), 4 methoxycarbophenyl phenylboronic acid (6.19 g, 34.4 mmol), [Pd CI (dppf)] / dichloromethane complex (1: 1) (1 · 39g, 1.72mmol), tripotassium phosphate (
2 2
水和物） (27.5g, 10.3mmol)及び 1, 4 ジォキサン（200ml)の混合液を、窒素 気流下、 80°Cで 17時間撹拌した。反応液を室温に冷却後、不溶物をセライトを用い たろ過で除去した。ろ液を減圧濃縮し、得られた残留物をシリカゲルクロマトグラフィ 一に付し、酢酸ェチル溶出部より得た分画を減圧濃縮して標記化合物（4.33g, 44Hydrate) (27.5 g, 10.3 mmol) and 1,4 dioxane (200 ml) were stirred at 80 ° C. for 17 hours under a nitrogen stream. The reaction solution was cooled to room temperature, and the insoluble material was removed by filtration using celite. The filtrate was concentrated under reduced pressure, the obtained residue was subjected to silica gel chromatography, and the fraction obtained from the eluate of ethyl acetate was concentrated under reduced pressure to give the title compound (4.33 g, 44
%)を得た。 %).
NMR(DMSO-d ) δ :3.87(3H, s), 7.47(1H, d, J = 9.4Hz) , 8.08 (2H,  NMR (DMSO-d) δ: 3.87 (3H, s), 7.47 (1H, d, J = 9.4Hz), 8.08 (2H,
6  6
d, J = 8.8Hz), 8.26 (2H, d, J = 8.8Hz) , 8.31(1H, d, J = 9.4Hz) , 8.44 ( 1H, s). MS (LC) m/z： 288 (M+ + H) . d, J = 8.8Hz), 8.26 (2H, d, J = 8.8Hz), 8.31 (1H, d, J = 9.4Hz), 8.44 (1H, s). MS (LC) m / z: 288 (M + + H).
(工程 2) 4—（6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル)安息香酸  (Step 2) 4- (6 Chloroimidazo [1, 2—b] pyridazine 3 yl) benzoic acid
[0348] [化 118] [0348] [Chemical 118]
Figure imgf000127_0001
Figure imgf000127_0001
[0349] 4一（6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル）安息香酸 メチル エステル [0349] 4 (6 Chloroimidazo [1,2-b] pyridazine 3 yl) benzoic acid methyl ester
(lOOmg, 0. 348mmol)、THF/水混合液（6 : 1 , 35ml)、水酸化リチウム一水和 物（29mg, 0. 695mmol)及び水（5ml)の混合液を、室温で 6時間撹拌した。反応 混合液に水酸化リチウム一水和物（15mg, 0. 347mmol)を追加し、室温でさらに 1 4時間攪拌した後、減圧下に THFを留去した。得られた残留物に 1N塩酸を加えて p H2とし、析出固形物をろ取、減圧乾燥して標記化合物（81. 6mg, 86%)を得た。 NMR(DMSO-d ) δ : 7. 47 (1H, d, J = 9. 4Hz) , 8. 07 (2H, d, J = 8. 4Hz) , (lOOmg, 0.348 mmol), THF / water mixture (6: 1, 35 ml), lithium hydroxide monohydrate (29 mg, 0.695 mmol) and water (5 ml) were stirred at room temperature for 6 hours. did. Lithium hydroxide monohydrate (15 mg, 0.347 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 14 hours, and then THF was distilled off under reduced pressure. 1N Hydrochloric acid was added to the obtained residue to adjust to pH 2, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (81.6 mg, 86%). NMR (DMSO-d) δ: 7.47 (1H, d, J = 9.4Hz), 8.07 (2H, d, J = 8.4Hz),
8. 24 (2H, d, J = 8. 4Hz) , 8. 32 (1H, d, J = 9. 4Hz) , 8. 44 (1H, s) . 8.24 (2H, d, J = 8.4Hz), 8.32 (1H, d, J = 9.4Hz), 8.44 (1H, s).
MS (LC) m/z： 274 (M+ + H) . MS (LC) m / z: 274 (M + + H).
(工程 3) 4— [6—(ペンジノレアミノ)イミダゾ [1 , 2— b]ピリダジンー3—ィル] (2S) ピロリジン 2—ィルメチル]ベンズアミド ギ酸塩  (Step 3) 4- [6- (Pendinoreamino) imidazo [1, 2-b] pyridazine-3-yl] (2S) Pyrrolidine 2-ylmethyl] benzamide formate
[0350] [化 119]  [0350] [Chemical 119]
Figure imgf000127_0002
[0351] 4一（6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル）安息香酸（35mg, 0. 128 mmol)、ペンジノレアミン（0. 0610ml, 0. 512mmol)及び DIEA (0. 134ml, 0. 76 7mmol)の混合液を、 120°Cで 30分間攪拌した。さらにベンジルァミン（0. 100ml, 0. 839mmol)を追加し、 120°Cで 22. 5時間攪拌した。反応混合液を室温に冷却 後、分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセト 二トリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。得られた濃縮残渣に (2S )—(アミノメチノレ）ピロリジン一 1—カルボン酸 tert ブチノレ エステル（0· 0418ml , 0. 256mmol)、 TEA(0. 027ml, 0. 192mmol)、 O ベンゾトリァゾーノレ— 1— ィノレ一 N, N, Ν' , Ν， 一テトラメチルゥロニゥム へキサフルォロホスフェート（0· 073 g, 0. 192mmol)及び DMF (2ml)を加え、室温で 85時間撹拌した。反応混合物を 減圧濃縮後、濃縮残渣を分取 HPLC (カラム： NOMURA Develosil Combi— R P— 5、移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。得ら れた濃縮残渣をジクロロメタン（lml)に溶解し、トリフルォロ酢酸（lml)を加えて 160 分間撹拌した。反応液を減圧濃縮し、得られた残渣を分取 HPLC (カラム： NOMUR A Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し、 目 的分画を減圧濃縮して標記化合物（6. 70mg, 11 %)を得た。
Figure imgf000127_0002
[0351] 4 (6 Chloroimidazo [1,2-b] pyridazine 3-yl) benzoic acid (35 mg, 0.128 mmol), pendinoleamine (0.0610 ml, 0.512 mmol) and DIEA (0. 134 ml, 0 76 7 mmol) was stirred at 120 ° C. for 30 minutes. Further, benzylamine (0. 100 ml, 0.839 mmol) was added, and the mixture was stirred at 120 ° C for 22.5 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile, water / formic acid), and the target fraction was concentrated under reduced pressure. To the resulting concentrated residue, (2S)-(aminomethinole) pyrrolidine mono-1-carboxylic acid tert-butylinyl ester (0 · 0418 ml, 0.256 mmol), TEA (0.027 ml, 0.192 mmol), O benzotriazonole 1 —Inole 1 N, N, Ν ′, Ν, 1 Tetramethyluronium Hexafluorophosphate (0 · 733 g, 0.192 mmol) and DMF (2 ml) were added and stirred at room temperature for 85 hours. After the reaction mixture was concentrated under reduced pressure, the concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. The obtained concentrated residue was dissolved in dichloromethane (lml), trifluoroacetic acid (lml) was added, and the mixture was stirred for 160 minutes. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: NOMUR A Develosil Combi— RP-5, mobile phase: acetonitrile / water / formic acid). The compound (6. 70 mg, 11%) was obtained.
MS (LC) m/z： 427 (M+ + H) .  MS (LC) m / z: 427 (M + + H).
[実施例 27] 4— [6 （シクロペンチルァミノ）イミダゾ [1 , 2— b]ピリダジン 3 ィ ノレ] -N- [2—（ジェチルァミノ）ェチル]ベンズアミド 2塩酸塩  [Example 27] 4— [6 (Cyclopentylamino) imidazo [1,2-b] pyridazine 3-ino] -N- [2- (Jetylamino) ethyl] benzamide dihydrochloride
(工程 1) 4 [6—クロロイミダゾ [1 , 2— b]ピリダジンー3—ィル]—N—[2—（ジェ チルァミノ）ェチル]ベンズアミド  (Step 1) 4 [6-Chloroimidazo [1,2-b] pyridazine-3-yl] —N— [2- (Jetylamino) ethyl] benzamide
[0352] [化 120] [0352] [Chemical 120]
Figure imgf000128_0001
[0353] [実施例 26]に記載の 4一（6 クロロイミダゾ [1, 2— b]ピリダジン 3 ィル)安息 香酸（0· 985g, 3.60mmol)及び DMF(50ml)の混合液に、 N, N ジェチルェ チレンジァミン（0.57ml, 3.9611111101)及び4ー（4, 6 ジメトキシ 1, 3, 5 トリア ジン一 2 ィル） 4 メチルモルホリニゥム クロリド（1. 17g, 4.68mmol)をカロえ、 室温で 145分間攪拌した。反応混合物を減圧濃縮し、濃縮残渣をシリカゲルカラムク 口マトグラフィー（溶出液：クロ口ホルム/メタノール/水混合液（7 :3:1)の下層）で精 製した。 目的分画を減圧濃縮して標記化合物（1.43g, 100%)を得た。
Figure imgf000128_0001
[0353] A mixture of 4 (6 chloroimidazo [1,2-b] pyridazine 3 yl) benzoic acid (0 · 985 g, 3.60 mmol) and DMF (50 ml) described in [Example 26] N, N Jetleche diendiamine (0.57ml, 3.9611111101) and 4- (4,6 dimethoxy 1,3,5 triazine-2-yl) 4 methylmorpholinum chloride (1.17g, 4.68mmol), Stir at room temperature for 145 minutes. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was purified by silica gel column chromatography (eluent: lower layer of chloroform / formaldehyde / methanol / water mixture (7: 3: 1)). The target fraction was concentrated under reduced pressure to obtain the title compound (1.43 g, 100%).
NMR(DMSO-d ) δ :1.20 (6Η, t, J = 7. OHz) , 3.02— 3. 19(6H, m) , 3.  NMR (DMSO-d) δ: 1.20 (6Η, t, J = 7. OHz), 3.02— 3. 19 (6H, m), 3.
6  6
58-3.67(2H, m) , 7.46(1H, d, J = 9.5Hz) , 8.06 (2H, d, J = 8.5Hz) , 8 .22 (2H, d, J = 8.5Hz), 8.32(1H, d, J = 9.5Hz) , 8.43(1H, s) , 8.95(1 H, br s).  58-3.67 (2H, m), 7.46 (1H, d, J = 9.5Hz), 8.06 (2H, d, J = 8.5Hz), 8.22 (2H, d, J = 8.5Hz), 8.32 (1H , d, J = 9.5Hz), 8.43 (1H, s), 8.95 (1 H, br s).
MS (LC) m/z： 372 (M+ + H) . MS (LC) m / z: 372 (M + + H).
(工程 2) 4— [6 （シクロペンチルァミノ）イミダゾ [1, 2— b]ピリダジン 3 ィル] N— [2—（ジェチルァミノ）ェチル]ベンズアミド 2塩酸塩  (Step 2) 4— [6 (Cyclopentylamino) imidazo [1,2-b] pyridazine 3-yl] N— [2- (Jetylamino) ethyl] benzamide dihydrochloride
[0354] [化 121] [0354] [Chemical 121]
Figure imgf000129_0001
Figure imgf000129_0001
4 [6 クロロイミダゾ [ 1 , 2— b]ピリダジン 3 ィル] N— [2 （ジェチルァミノ )ェチノレ]ベンズアミド（0· 375g, 1. Olmmol)及びシクロペンチルァミン（2.5ml, 2 5.3mmol)の混合液を、 145°Cで 13時間撹拌した。反応混合液を減圧濃縮し、得ら れた残渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相 ：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。得られた濃縮残渣 に IN塩酸 (エタノール溶液）を加え減圧濃縮した。得られた固形物を酢酸ェチルで 洗浄後、減圧乾燥して標記化合物（0.276g, 60%)を得た。 4 [6 Chloroimidazo [1, 2— b] pyridazine 3 yl] N— [2 (Jetylamino) ethinole] benzamide (0 · 375 g, 1. Olmmol) and cyclopentylamine (2.5 ml, 2 5.3 mmol) mixed The solution was stirred at 145 ° C for 13 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. The resulting concentrated residue IN hydrochloric acid (ethanol solution) was added thereto, and the mixture was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate and dried under reduced pressure to obtain the title compound (0.276 g, 60%).
NMR(DMSO-d ) δ :1.24 (6Η, t, J = 7. OHz) , 1.56— 1.77(6H, m) , 1.  NMR (DMSO-d) δ: 1.24 (6Η, t, J = 7. OHz), 1.56— 1.77 (6H, m), 1.
6  6
97-2.06 (2H, m), 3.15— 3.28 (6H, m) , 3.68 (2H, dd, J=ll.7, 5.9H z), 4.01-4.10(1H, m), 7.19(1H, d, J = 8.5Hz) , 7.83 7.90(1H, m) , 8.02(1H, d, J = 8.5Hz), 8.09 (2H, d, J = 7.3Hz) , 8.32 (2H, d, J = 7.3 Hz), 8.51(1H, s), 9.06(1H, t, J = 4.9Hz) , 10.31(1H, br s) .  97-2.06 (2H, m), 3.15— 3.28 (6H, m), 3.68 (2H, dd, J = ll.7, 5.9H z), 4.01-4.10 (1H, m), 7.19 (1H, d, J = 8.5Hz), 7.83 7.90 (1H, m), 8.02 (1H, d, J = 8.5Hz), 8.09 (2H, d, J = 7.3Hz), 8.32 (2H, d, J = 7.3 Hz), 8.51 (1H, s), 9.06 (1H, t, J = 4.9Hz), 10.31 (1H, br s).
MS(LC)m/z:421.6(M+ + H). MS (LC) m / z: 421.6 (M + + H).
[実施例 28] 4— [6 （ブチルァミノ）イミダゾ [1, 2— b]ピリダジン 3 ィル] N 一 [ [ (2S) 1 メチルピロリジン 2—ィル]メチル]ベンズアミド ギ酸塩  [Example 28] 4- [6 (Butylamino) imidazo [1,2-b] pyridazine 3-yl] N-[[(2S) 1-methylpyrrolidine-2-yl] methyl] benzamide formate
(工程 1) 4 [6 クロロイミダゾ [1, 2— b]ピリダジンー3 ィル]—N—[[(2S)—1 一（tert ブトキシカルボニル）ピロリジンー2—ィル]メチル]ベンズアミド (Step 1) 4 [6 Chloroimidazo [1, 2-b] pyridazine-3-yl] -N-[[(2S) -1 mono (tert-butoxycarbonyl) pyrrolidine-2-yl] methyl] benzamide
[化 122] [Chemical 122]
Figure imgf000130_0001
Figure imgf000130_0001
[実施例 26]に記載の 4一（6 クロロイミダゾ [1, 2— b]ピリダジン一 3 ィル)安息 香酸（2· 20g, 8.04mmol)の DMF(lOOml)溶 ί夜に、（2S)— 2 （アミノメチノレ）ピ 口リジン— 1—カルボン酸 tert ブチル エステル（1· 53ml, 8.04mmol)及び 4 — (4, 6 ジメトキシ一 1, 3, 5 トリァジン一 2 ィル） 4 メチルモルホリニゥム ク ロリド（2. llg, 8.44mmol)を加え、室温で 19時間攪拌した。反応混合物を減圧濃 縮した。濃縮残渣をシリカゲルクロマトグラフィーに付し、クロ口ホルム：メタノール =2 0:1溶出部より得た分画を減圧濃縮して、標記化合物（2.84g, 78%)を得た。 NMR(DMSO-d ) δ :1.39 (9Η, s), 1.72— 1.91 (5H, m) , 3.19— 3.30 ( 2H, m), 3.88-4.02(1H, m) , 7.44(1H, d, J = 9.5Hz) , 7.92— 8.01(3 H, m), 8.19(2H, d, J = 8.3Hz) , 8.29(1H, d, J = 9.5Hz) , 8.40(1H, s) , 8.59(1H, t, J = 5.4Hz). 4) (6 Chloroimidazo [1,2-b] pyridazine-1 3 yl) benzoic acid (2.20 g, 8.04 mmol) described in [Example 26] in DMF (lOOml) solution at night (2S ) — 2 (aminomethinole) pi-lysine — 1-carboxylic acid tert butyl ester (1.53 ml, 8.04 mmol) and 4 — (4, 6 dimethoxy-1,3,5 triazine-2-yl) 4 methylmorpholinium Murochloride (2.llg, 8.44mmol) was added and stirred at room temperature for 19 hours. The reaction mixture was concentrated under reduced pressure. The concentrated residue was subjected to silica gel chromatography, and the fraction obtained from the eluate of black mouth form: methanol = 20: 1 was concentrated under reduced pressure to obtain the title compound (2.84 g, 78%). NMR (DMSO-d) δ: 1.39 (9Η, s), 1.72— 1.91 (5H, m), 3.19— 3.30 ( 2H, m), 3.88-4.02 (1H, m), 7.44 (1H, d, J = 9.5Hz), 7.92— 8.01 (3 H, m), 8.19 (2H, d, J = 8.3Hz), 8.29 ( 1H, d, J = 9.5Hz), 8.40 (1H, s), 8.59 (1H, t, J = 5.4Hz).
MS(LC)m/z:456.6(M+ + H). MS (LC) m / z: 456.6 (M + + H).
(工程 2) 4— [6 クロロイミダゾ [1, 2— b]ピリダジンー3 ィル]—N—[[(2S)—1 メチルピロリジン 2—ィル]メチル]ベンズアミド  (Step 2) 4— [6 Chloroimidazo [1,2-b] pyridazine-3-yl] —N — [[(2S) -1 Methylpyrrolidine 2-yl] methyl] benzamide
[化 123] [Chemical 123]
Figure imgf000131_0001
Figure imgf000131_0001
4一 [6 クロロイミダゾ [ 1 , 2— b]ピリダジン一 3 ィル]一 N— [ [ (2S)— 1一 （tert ブトキシカルボ二ノレ）ピロリジンー2 ィノレ]メチノレ]ベンズアミド（2.84g, 6.24m mol)、ジクロロメタン（40ml)及びトリフルォロ酢酸（10ml)の混合液を、室温で 2· 5 時間撹拌した。反応液を減圧濃縮した。得られた残渣をメタノール（10ml)に溶解し 、酢酸（8ml)、 37%ホルムアルデヒド水溶液（5.07ml, 62.4mmol)、シァノ水素 化ホウ素ナトリウム（3.92g, 62.4mmol)を加えて室温で 2時間撹拌した。反応液を 飽和炭酸水素ナトリウム水溶液に注ぎ込み、ジクロロメタンで抽出した。抽出液を水 及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。不溶物をろ過後、ろ液を 減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（溶出液：クロロホ ルム/メタノール/水混合液（7 :3:1)の下層）で精製し、 目的分画を減圧濃縮して 標記化合物（1· 93g, 84%)を得た。 4 1 [6 Chloroimidazo [1, 2— b] pyridazine 1 3 yl] 1 N— [[(2S) — 1 1 (tert butoxycarboninole) pyrrolidine-2 inore] methinore] benzamide (2.84 g, 6.24 m mol), dichloromethane (40 ml) and trifluoroacetic acid (10 ml) were stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure. The obtained residue was dissolved in methanol (10 ml), acetic acid (8 ml), 37% aqueous formaldehyde solution (5.07 ml, 62.4 mmol) and sodium cyanoborohydride (3.92 g, 62.4 mmol) were added, and the mixture was stirred at room temperature for 2 hours. did. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: lower layer of chloroform / methanol / water mixture (7: 3: 1)), and the target fraction was concentrated under reduced pressure to give the title compound (1.93 g, 84%).
NMR(DMSO-d ) δ :1.55— 1.70 (4Η, m) , 1.82— 1.93(1Η, m) , 2.16  NMR (DMSO-d) δ: 1.55— 1.70 (4 Η, m), 1.82— 1.93 (1 Η, m), 2.16
6  6
-2.28(1Η, m), 2.37(3Η, br s) , 3.00(1Η, br s) , 3. 14— 3.25(1Η, m ), 3.46-3.54(1Η, m) , 7.46(1Η, d, J = 9.4Hz) , 7.99 (2Η, d, J = 8.5Η ζ), 8.20 (2Η, d, J = 8.5Hz), 8.32(1Η, d, J = 9.4Hz) , 8.41(1Η, s) , 8.4 9(1Η, t, J = 6.6Hz). MS (LC) m/z： 370 (M+ + H) . -2.28 (1Η, m), 2.37 (3Η, br s), 3.00 (1Η, br s), 3.14— 3.25 (1Η, m), 3.46-3.54 (1Η, m), 7.46 (1Η, d, J = 9.4Hz), 7.99 (2Η, d, J = 8.5Η ζ), 8.20 (2Η, d, J = 8.5Hz), 8.32 (1Η, d, J = 9.4Hz), 8.41 (1Η, s), 8.4 9 (1Η, t, J = 6.6Hz). MS (LC) m / z: 370 (M + + H).
(工程 3) 4— [6 （ブチルァミノ)イミダゾ [1 , 2— b]ピリダジン 3 ィル] N— [ [ (2S) 1 メチルピロリジンー2—ィル]メチル]ベンズアミド ギ酸塩  (Step 3) 4— [6 (Butylamino) imidazo [1, 2— b] pyridazine 3 yl] N— [[(2S) 1 Methylpyrrolidine-2-yl] methyl] benzamide formate
[0360] [化 124] [0360] [Chemical 124]
Figure imgf000132_0001
Figure imgf000132_0001
[0361] 4 [6 クロロイミダゾ [1 , 2— b]ピリダジンー3 ィル]ーN—[ [ (2S)—lーメチル ピロリジンー2 ィル]メチノレ]ベンズアミド（0· 030g, 0. 081 lmmol)及びブチルァ ミン（0. 0593ml, 0. 81 lmmol)の混合液を、 85。Cで 18. 5時間、 100。Cで 13. 5 時間、さらに 120°Cで 13. 5時間撹拌した。反応混合物を室温に冷却後、分取 HPL C (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ ギ酸)で精製し、 目的分画を減圧濃縮して標記化合物（14. 6mg, 40%)を得た。 [0361] 4 [6 Chloroimidazo [1, 2—b] pyridazine-3-yl] -N — [[(2S) -l-methylpyrrolidine-2-yl] methinole] benzamide (0 · 030 g, 0.081 lmmol) and 85. Mixture of butyramine (0.0593 ml, 0.81 lmmol). 18.5 hours at C, 100. The mixture was stirred at C for 13.5 hours and further at 120 ° C for 13.5 hours. The reaction mixture was cooled to room temperature and purified by preparative HPL C (column: NOMURA Develosil Combi— RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure to give the title compound (14.6 mg). , 40%).
MS (LC) m/z： 204 (M+ + H) .  MS (LC) m / z: 204 (M + + H).
[実施例 29] 4— [6— [ (3, 4 ジクロ口ベンジル)ァミノ]イミダゾ [1 , 2— b]ピリダジ ンー3—ィル] -N- [3—（ジメチルァミノ）プロピル]ベンズアミド ギ酸塩  [Example 29] 4— [6— [(3,4 Diclochiobenzyl) amino] imidazo [1,2-b] pyridazine-3-yl] -N- [3- (dimethylamino) propyl] benzamide formate
[0362] [化 125] [0362] [Chemical 125]
■HC02H
Figure imgf000132_0002
[0363] [実施例 1]に記載の 4 [6— [ (3, 4 ジクロ口ベンジル）ァミノ]イミダゾ [1 , 2— b] ピリダジンー3 ィノレ]安息香酸（20mg, 0. 0484mmol)、 N, N ジメチルー 1 , 3 —プロノ ンジァミン（0. 0061ml, 0. 0484mmol)、 TEA(0. 0068ml, 0. 0484m mol)及び DMF (0. 5ml)の混合液に、 BOP (18mg, 0. 0484mmol)をカロえ、室温 で 24時間攪拌した。反応混合物を減圧濃縮した。得られた濃縮残渣を分取 HPLC ( カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ 酸)で精製し、 目的分画を減圧濃縮して標記化合物（12. 4mg, 47%)を得た。 MS (LC) m/z： 497 (M+ + H) . ■ HC0 2 H
Figure imgf000132_0002
[0363] 4 [6— [(3, 4 Dichloroguchi benzyl) amino] imidazo [1, 2— b] pyridazine-3-inore] benzoic acid (20 mg, 0.0484 mmol), N, N Dimethyl-1,3-pronandamine (0.00061 ml, 0.0484 mmol), TEA (0.0065 ml, 0.0484 mmol) and DMF (0.5 ml) were mixed with BOP (18 mg, 0.0484 mmol). Calorie and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The resulting concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi— RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure to give the title compound (12.4 mg, 47 %). MS (LC) m / z: 497 (M + + H).
[実施例 30] N—（1 ベンジルピペリジン 4 ィル） 4 [6— [ (3, 4 ジクロ口 ベンジル）ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィル]ベンズアミド ギ酸塩  [Example 30] N— (1 benzylpiperidine 4 yl) 4 [6— [(3, 4 Dicloccyl benzyl) amino] imidazo [1, 2— b] pyridazine 3 yl] benzamide formate
[0364] [化 126] [0364] [Chemical 126]
Figure imgf000133_0001
Figure imgf000133_0001
[実施例 1]に記載の 4 [6— [ (3, 4 ジクロ口ベンジル）ァミノ]イミダゾ [1 , 2— b] ピリダジンー3 ィル]安息香酸（20mg, 0. 0484mmol)、 4 アミノー 1一べンジル ピぺリジン（0. 0099ml, 0. 0484mmol)、 TEA (0. 0068ml, 0. 0484mmol)及 び DMF (0. 5ml)の混合液に、 BOP (18mg, 0. 0484mmol)をカロえ、室温で 24時 間攪拌した。反応混合物を減圧濃縮した。得られた濃縮残渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精 製し、 目的分画を減圧濃縮して標記化合物（10. lmg, 33%)を得た。 4 [6— [(3,4 Dichlorodiethyl) amino] imidazo [1,2-b] pyridazine-3-yl] benzoic acid (20 mg, 0.0484 mmol), 4 amino-11 Carrying BOP (18 mg, 0.0484 mmol) into a mixture of benzylpiperidine (0.0099 ml, 0.0484 mmol), TEA (0.0065 ml, 0.0484 mmol) and DMF (0.5 ml), Stir at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The obtained concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure to give the title compound (10 lmg, 33 %).
MS (LC) m/z： 585 (M" + H) .  MS (LC) m / z: 585 (M "+ H).
[実施例 31] [4— (ピロリジン— 1—ィル）ピぺリジン— 1—ィル] = [4— [6— (3, 4 ージクロ口ベンジルァミノ）イミダゾ [1 , 2— b]ピリダジンー3 ィル]フエニル] =ケトン ギ酸塩 [Example 31] [4— (Pyrrolidine—1-yl) piperidine—1-yl] = [4— [6— (3, 4 -Dichlorinated benzylamino) imidazo [1, 2-b] pyridazine-3yl] phenyl] = ketone formate
[0366] [化 127]  [0366] [Chemical 127]
Figure imgf000134_0001
Figure imgf000134_0001
[0367] [実施例 1]に記載の 4 [6— [ (3, 4 ジクロ口ベンジル）ァミノ]イミダゾ [1 , 2— b] ピリダジンー3 ィル]安息香酸（20mg, 0. 0484mmol)、 4 （ピロリジンー1ーィル )ピペリジン（7. 5mg, 0. 0484mmol)、 TEA(0. 0068ml, 0. 0484mmol)及び D MF (0. 5ml)の混合液に、 BOP (18mg, 0. 0484mmol)をカロえ、室温で 24時間攪 拌した。反応混合液を減圧濃縮した。得られた濃縮残渣を分取 HPLC (カラム： NO MURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し 、 目的分画を減圧濃縮して標記化合物（10. 3mg, 36%)を得た。 [0367] 4 [6— [(3, 4 Dicyclochiabenzyl) amino] imidazo [1,2-b] pyridazine-3-yl] benzoic acid (20 mg, 0.0484 mmol), described in [Example 1], 4 (Pyrrolidine-1-yl) piperidine (7.5 mg, 0.0484 mmol), TEA (0.0065 ml, 0.0484 mmol) and DMF (0.5 ml) were mixed with BOP (18 mg, 0.0484 mmol). The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure. The resulting concentrated residue was purified by preparative HPLC (column: NO MURA Develosil Combi— RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure to give the title compound (10.3 mg, 36 %).
MS (LC) m/z： 549 (M+ + H) .  MS (LC) m / z: 549 (M + + H).
[実施例 32] 4— [6— (N メチルァミノ)イミダゾ [1 , 2— b]ピリダジン— 3 ィル]― N- [ (2S) ピロリジン 2—ィルメチル]ベンズアミド ギ酸塩  [Example 32] 4- [6— (N-methylamino) imidazo [1,2-b] pyridazine-3-yl] -N-[(2S) pyrrolidine 2-ylmethyl] benzamide formate
[0368] [化 128] [0368] [Chemical 128]
Figure imgf000134_0002
[0369] [実施例 26]に記載の 4一（6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル)安息 香酸（35mg, 0. 128mmol)、 2Mメチノレアミン（THF溶 ί夜） (0. 256ml, 0. 512m mol)及び DIEA(0. 134ml, 0. 767mmol)の混合液を、 120。Cで 30分間攪拌した 。さらに 2Mメチノレアミン（THF溶 ί夜） (0. 100ml, 0. 200mmol)をカロえ、 120。Cで 2 2. 5時間攪拌した。反応液を室温に冷却後、減圧濃縮した。残渣を分取 HPLC (力 ラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸 )で精製し、 目的分画を減圧濃縮した。得られた濃縮残渣に（2S)— 2— (ァミノメチル )ピロリジン一 1—カルボン酸 tert ブチノレ エステル（0. 0418ml, 0. 256mmol) 、 TEA (0. 027ml, 0. 192mmol)、 O ベンゾトリアゾール 1 ィル— N, N, N， , N，一テトラメチルゥロニゥム へキサフルォロホスフェート（73mg, 0. 192mmol) 及び DMF (2ml)を加え、室温で 85時間攪拌した。反応混合物を減圧濃縮し、濃縮 残渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァ セトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。得られた濃縮残渣を ジクロロメタン（lml)に溶解し、トリフルォロ酢酸（lml)を加えて 160分間攪拌した。 反応液を減圧濃縮して得られた残渣を分取 HPLC (カラム： NOMURA Develosil
Figure imgf000134_0002
[0369] 4- (6-chloroimidazo [1,2-b] pyridazine 3 yl) benzoic acid (35 mg, 0.128 mmol), 2M methenoreamine (THF dissolved overnight) described in [Example 26] (0 256 ml, 0.512 mmol) and DIEA (0.134 ml, 0.7767 mmol). Stir at C for 30 minutes. Further, add 2M methinoreamine (THF solution) (0. 100ml, 0.200mmol), 120. The mixture was stirred at C for 22.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC (force ram: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. The concentrated residue thus obtained was mixed with (2S) -2- (aminomethyl) pyrrolidine 1-carboxylic acid tert-butanolate (0.0418 ml, 0.256 mmol), TEA (0.027 ml, 0.192 mmol), O benzotriazole 1 Lu, N, N, N,, N, monotetramethyluronium hexafluorophosphate (73 mg, 0.192 mmol) and DMF (2 ml) were added, and the mixture was stirred at room temperature for 85 hours. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. The obtained concentrated residue was dissolved in dichloromethane (lml), trifluoroacetic acid (lml) was added, and the mixture was stirred for 160 minutes. The residue obtained by concentrating the reaction solution under reduced pressure was subjected to preparative HPLC (column: NOMURA Develosil
Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し、 目的分画を減圧 濃縮して標記化合物（12. Omg, 24%)を得た。 Combi—RP-5, mobile phase: acetonitrile / water / formic acid) and the target fraction was concentrated under reduced pressure to give the title compound (12. Omg, 24%).
MS (LC) m/z： 351 (M+ + H) . MS (LC) m / z: 351 (M + + H).
[実施例 33] 4— [6— [ (3 ヒドロキシプロピル）ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィル]ーN—[ (2S)—ピロリジンー2 ィルメチル]ベンズアミド ギ酸塩  [Example 33] 4— [6 — [(3 Hydroxypropyl) amino] imidazo [1,2-b] pyridazine 3-yl] -N — [(2S) -pyrrolidine-2-ylmethyl] benzamide formate
[0370] [化 129] [0370] [Chemical 129]
Figure imgf000135_0001
[0371] [実施例 26]に記載の 4一（6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル)安息 香酸（35mg, 0. 128mmol)、 3 アミノー 1 プロノ ノーノレ（0. 0430ml, 0. 512m mol)及び DIEA(0. 134ml, 0. 767mmol)の混合液を、 120。Cで 30分間攪拌した 。さらに 3 アミノー 1ープロノ ノーノレ（0. 100ml, 1. 19mmol)を追カロし、 120°Cで 2 2. 5時間攪拌した。反応液を室温に冷却後、減圧濃縮して得られた残渣を分取 HP LC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水 /ギ酸)で精製し、 目的分画を減圧濃縮した。得られた濃縮残渣に（2S)— 2— (アミ ノメチノレ）ピロリジン一 1—カルボン酸 tert ブチノレ エステル（0. 0418ml, 0. 25 6mmol)、 ΤΕΑ(0· 027ml, 0. 192mmol)、 O ベンゾトリアゾール 1 ィル— N , N, N， ， N， 一テトラメチルゥロニゥム へキサフルォロホスフェート（73mg, 0. 192 mmol)及び DMF (2ml)を加え、室温で 85時間攪拌した。反応混合物を減圧濃縮 し、濃縮残渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移 動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。得られた濃縮 残渣をジクロロメタン（lml)に溶解し、トリフルォロ酢酸（lml)を加えて 160分間攪拌 した。反応液を減圧濃縮し、得られた残渣を水/メタノール混合液（0. 5ml/0. 5ml )に溶解し、炭酸カリウム（26mg, 0. 192mmol)を加えて 50°Cで 24時間攪拌した。 反応混合物をろ過し、ろ液を減圧濃縮して得られた残渣を分取 HPLC (カラム： NO MURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し 、 目的分画を減圧濃縮して標記化合物（10. Omg, 18%)を得た。
Figure imgf000135_0001
[0371] 4-1- (6 chloroimidazo [1,2-b] pyridazine 3 yl) benzoic acid (35 mg, 0.128 mmol), 3 amino-1 prono nore (0.0430 ml, 0. 512 mmol) and DIEA (0.134 ml, 0. 767 mmol), 120. Stir at C for 30 minutes. Further, 3 amino-1-prono norole (0. 100 ml, 1.19 mmol) was added and stirred at 120 ° C. for 22.5 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by preparative HP LC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the desired fraction is reduced in pressure. Concentrated. To the concentrated residue obtained, (2S) -2- (aminomethinole) pyrrolidine mono-1-carboxylic acid tert-butylenoester (0.0418 ml, 0.25 6 mmol), ΤΕΑ (0 · 027 ml, 0.192 mmol), O benzotriazole 1il—N, N, N, N, monotetramethyluronium hexafluorophosphate (73 mg, 0.192 mmol) and DMF (2 ml) were added and stirred at room temperature for 85 hours. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. The obtained concentrated residue was dissolved in dichloromethane (lml), trifluoroacetic acid (lml) was added, and the mixture was stirred for 160 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in a water / methanol mixture (0.5 ml / 0.5 ml), potassium carbonate (26 mg, 0.192 mmol) was added, and the mixture was stirred at 50 ° C. for 24 hours. . The reaction mixture was filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by preparative HPLC (column: NO MURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid). Concentration under reduced pressure gave the title compound (10. Omg, 18%).
MS (LC) m/z： 395 (M+ + H) . MS (LC) m / z: 395 (M + + H).
[実施例 34 ] 4— [ 6— [ [ 3 （ 1 H—イミダゾ—ルー 1 ィル)プロピル]ァミノ]イミダ ゾ [ 1 , 2— b]ピリダジン 3 ィル] N— [ (2S) ピロリジン一 2 ィルメチル]ベン ズアミド ギ酸塩  [Example 34] 4— [6— [[3 (1 H—Imidazolu 1 yl) propyl] amino] imidazo [1, 2— b] Pyridazine 3 yl] N— [(2S) pyrrolidine 2ylmethyl] benzamide formate
[0372] [化 130]
Figure imgf000137_0001
[0372] [Chemical 130]
Figure imgf000137_0001
[実施例 26]に記載の 4一（6 クロロイミダゾ [1 , 2— b]ピリダジン一 3 ィル)安息 香酸（35mg, 0. 128mmol)、 3— (1H イミダゾ一ルー 1—ィノレ）プロピルアミン（0 . 0710ml, 0. 512mmol)及び DIEA(0. 134ml, 0. 767mmol)の混合液を、 12 0°Cで 30分間攪拌した。さらに 3— (1H イミダゾ—ル— 1—ィル）プロピルアミン（0· 100ml, 0. 721mmol)を追加し、 120°Cで 22. 5時間攪拌した。反応液を室温に冷 却後、分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァ セトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。得られた濃縮残渣に（ 2S)— 2—（アミノメチル）ピロリジン 1一力ルボン酸 tert ブチル エステル（0· 0 418ml, 0. 256mmol)、 TEA (0. 027ml, 0. 192mmol)、 O ベンゾトリァゾーノレ — 1—ィノレ一 N, N, Ν' , Ν， 一テトラメチルゥロニゥム へキサフルォロホスフェート（7 3mg, 0. 192mmol)及び DMF (2ml)を加え、室温で 85時間攪拌した。反応混合 物を減圧濃縮後、濃縮残渣を分取 HPLC (カラム： NOMURA Develosil Combi RP— 5、移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮した。 得られた濃縮残渣をジクロロメタン（lml)に溶解し、トリフルォロ酢酸（lml)を加えて 160分間攪拌した。反応液を減圧濃縮し、得られた残渣を分取 HPLC (カラム: NO MURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し 、 目的分画を減圧濃縮して標記化合物（12. lmg, 18%)を得た。 4- (6-chloroimidazo [1,2-b] pyridazine-1-yl) benzoic acid (35 mg, 0.128 mmol), 3- (1H imidazol-l-inore) propyl described in [Example 26] A mixture of amine (0.0710 ml, 0.512 mmol) and DIEA (0.134 ml, 0.7767 mmol) was stirred at 120 ° C. for 30 minutes. Further, 3- (1H imidazol-1-yl) propylamine (0 · 100 ml, 0.721 mmol) was added, and the mixture was stirred at 120 ° C. for 22.5 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. To the resulting concentrated residue, (2S) -2- (aminomethyl) pyrrolidine 1-strength rubonic acid tert butyl ester (0 · 0 418 ml, 0.256 mmol), TEA (0.027 ml, 0.192 mmol), O benzotria Zonole — 1—Inole 1 N, N, Ν ', Ν, 1 Tetramethyluronium Hexafluorophosphate (73 mg, 0.192 mmol) and DMF (2 ml) were added and stirred at room temperature for 85 hours did. After the reaction mixture was concentrated under reduced pressure, the concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. The obtained concentrated residue was dissolved in dichloromethane (lml), trifluoroacetic acid (lml) was added, and the mixture was stirred for 160 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: NO MURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure to give the title compound. (12. lmg, 18%) was obtained.
MS (LC) m/z： 445 (M" + H) . MS (LC) m / z: 445 (M "+ H).
[実施例 35] 4— [6— [ [2 （ァセチルァミノ）ェチル]ァミノ]イミダゾ [1 , 2— b]ピリ ダジン 3 ィル]ーN—[ (2S)—ピロリジンー2 ィルメチル]ベンズアミド ギ酸塩 [化 131] [Example 35] 4- [6 — [[2 (Acetylamino) ethyl] amino] imidazo [1,2, -b] pyridazine 3yl] -N — [(2S) -pyrrolidine-2-ylmethyl] benzamide formate [Chemical 131]
Figure imgf000138_0001
Figure imgf000138_0001
[実施例 26]に記載の 4一（6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル)安息 香酸（35mg, 0. 128mmol)、 N ァセチノレエチレンジァミン（0. 0580ml, 0. 512 mmol)及び DIEA(0. 134ml, 0. 767mmol)の混合液を、 120°Cで 30分間攪拌し た。さらに N ァセチノレエチレンジァミン（0. 100ml, 0. 883mmol)を追カロし、 120 °Cで 22. 5時間攪拌した。反応混合液を室温に冷却後、分取 HPLC (カラム： NOM URA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し、 目的分画を減圧濃縮した。得られた濃縮残渣に（2S)— 2—（アミノメチル)ピロリジン —1—カルボン酸 tert ブチノレ エステル（0. 0418ml, 0. 256mmol)、 TEA(0 • 027ml, 0. 192mmol)、 O ベンゾトリアゾール 1 ィル— N, Ν, Ν' , Ν， テト ラメチノレゥロニゥム へキサフルォロホスフェート（73mg, 0. 192mmol)及び DMF ( 2ml)を加え、室温で 85時間攪拌した。反応混合物を減圧濃縮後、濃縮残渣を分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリノレ /水/ギ酸)で精製し、 目的分画を減圧濃縮した。得られた濃縮残渣をジクロ口メタ ン（lml)に溶解し、トリフノレオ口酢酸（lml)を加えて 160分間攪拌した。反応液を減 圧濃縮し、得られた残渣を分取 HPLC (カラム： NOMURA Develosil Combi - RP— 5、移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮して標 記化合物（12· 2mg, 20%)を得た。 [Example 26] 4- (6-chloroimidazo [1,2-b] pyridazine 3 yl) benzoic acid (35 mg, 0.128 mmol), N-acetylenoethylenediamine (0.0580 ml, 0. 512 mmol) and DIEA (0.134 ml, 0. 767 mmol) were stirred at 120 ° C for 30 minutes. Further, N-acetylenoethylenediamine (0.100 ml, 0.883 mmol) was added and stirred at 120 ° C. for 22.5 hours. The reaction mixture was cooled to room temperature and then purified by preparative HPLC (column: NOM URA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. To the concentrated residue obtained, (2S) -2- (aminomethyl) pyrrolidine-1-carboxylic acid tert butynole ester (0.0418 ml, 0.256 mmol), TEA (0 • 027 ml, 0.192 mmol), O benzotriazole 1 Nyl, N, Ν, Ν ', テ, tetramethinoleuronium hexafluorophosphate (73 mg, 0.192 mmol) and DMF (2 ml) were added and stirred at room temperature for 85 hours. The reaction mixture was concentrated under reduced pressure, and the concentrated residue was purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure. The obtained concentrated residue was dissolved in diclonal methane (lml), trifnoreo oral acetic acid (lml) was added, and the mixture was stirred for 160 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: NOMURA Develosil Combi-RP-5, mobile phase: acetonitrile / water / formic acid). The compound (12.2 mg, 20%) was obtained.
MS (LC) m/z： 422 (M" + H) . MS (LC) m / z: 422 (M "+ H).
[実施例 36] 4— [6— [ (2, 2—ジメチルプロピル）ァミノ]イミダゾ [1 , 2— b]ピリダジ ン— 3—ィル] N— [[(2S)— 1—メチルピロリジン— 2—ィル]メチル]ベンズアミド ギ酸塩 [Example 36] 4— [6 — [(2,2-Dimethylpropyl) amino] imidazo [1,2, -b] pyridazi 3—yl] N — [[(2S) — 1-methylpyrrolidine-2-yl] methyl] benzamide formate
[0376] [化 132]  [0376] [Chemical 132]
Figure imgf000139_0001
Figure imgf000139_0001
[0377] [実施例 28]に記載の 4 [6 クロロイミダゾ [1, 2— b]ピリダジン 3 ィル] N [0377] 4 [6 Chloroimidazo [1, 2-b] pyridazine 3 yl] described in [Example 28] N
[[(2S)— 1ーメチノレピロリジン 2 ィノレ]メチノレ]ベンズアミド（30mg, 0.0811 mmol)及び 2, 2 ジメチルプロピルアミン（70· 7mg, 0.81 lmmol)の混合液を、 8 5°Cで 18.5時間、 100°Cで 13.5時間、さらに 120°Cで 13.5時間攪拌した。反応混 合物を室温に冷却後、分取 HPLC (カラム： NOMURA Develosil Combi— RP 5、移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮して標記化 合物（16· 2mg, 43%)を得た。  [[(2S) — 1-Metinolepyrrolidine 2-inole] methinole] benzamide (30 mg, 0.0811 mmol) and 2,2 dimethylpropylamine (70 · 7 mg, 0.81 lmmol) at 85 ° C for 18.5 hours The mixture was stirred at 100 ° C for 13.5 hours and further at 120 ° C for 13.5 hours. The reaction mixture is cooled to room temperature, purified by preparative HPLC (column: NOMURA Develosil Combi— RP 5, mobile phase: acetonitrile / water / formic acid), and the target fraction is concentrated under reduced pressure to give the title compound (16 · 2mg, 43%)
NMR(DMSO-d ) δ :0.99 (9Η, s), 1.55— 1.70 (3H, m) , 1.81— 1.93(  NMR (DMSO-d) δ: 0.99 (9Η, s), 1.55— 1.70 (3H, m), 1.81— 1.93 (
6  6
1H, m), 2.24(1H, q, J = 8.6Hz) , 2.38 (3H, s) , 2.46— 2.54(1H, m) , 2 .98-3.04(1H, m), 3.15— 3.53 (4H, m) , 6.84(1H, d, J = 9.8Hz) , 7.0 0(1H, t, J = 6.0Hz), 7.75(1H, d, J = 9.8Hz) , 7.93 (2H, d, J = 8.5Hz) , 7.98(1H, s), 8.17(1H, s) , 8.31 (2H, d, J = 8.5Hz) , 8.54— 8.46(1H, m) .  1H, m), 2.24 (1H, q, J = 8.6Hz), 2.38 (3H, s), 2.46—2.54 (1H, m), 2.98-3.04 (1H, m), 3.15—3.53 (4H, m), 6.84 (1H, d, J = 9.8Hz), 7.0 0 (1H, t, J = 6.0Hz), 7.75 (1H, d, J = 9.8Hz), 7.93 (2H, d, J = 8.5Hz) ), 7.98 (1H, s), 8.17 (1H, s), 8.31 (2H, d, J = 8.5Hz), 8.54-8.46 (1H, m).
MS (LC) m/z： 421 (M+ + H) . MS (LC) m / z: 421 (M + + H).
[実施例 37] 4— [6— [(シクロへキシル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3— ィル] N— [[( 2 S )— 1 メチルピロリジン 2—ィル]メチル]ベンズアミド ギ酸塩 [0378] [化 133] [Example 37] 4— [6 — [(Cyclohexyl) amino] imidazo [1, 2-b] pyridazine-3-yl] N — [[(2 S) — 1 Methylpyrrolidine 2-yl] methyl ] Benzamide formate [0378] [Chemical 133]
Figure imgf000140_0001
Figure imgf000140_0001
[0379] [実施例 28]に記載の 4 [6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル] N [0379] 4 [6 Chloroimidazo [1, 2—b] pyridazine 3 yl] described in [Example 28] N
[ [ (2S)— 1ーメチノレピロリジン 2 ィノレ]メチノレ]ベンズアミド（30mg, 0. 0811 mmol)及びシクロへキシルァミン（80. 4mg, 0. 81 lmmol)の混合液を、 85°Cで 18 . 5時間、 100°Cで 13. 5時間、さらに 120°Cで 13. 5時間攪拌した。反応混合物を室 温に冷却後、分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動 相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮して標記化合物（12. 5mg, 32%)を得た。  [[(2S) — 1-Methinorepyrrolidine 2-inole] methinole] benzamide (30 mg, 0.811 mmol) and cyclohexylamine (80.4 mg, 0.81 mmol) at 85 ° C. The mixture was stirred for 5 hours at 100 ° C for 13.5 hours and further at 120 ° C for 13.5 hours. The reaction mixture was cooled to room temperature, purified by preparative HPLC (column: NOMURA Develosil Combi— RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure to give the title compound (12.5 mg , 32%).
MS (LC) m/z： 433 (M+ + H) .  MS (LC) m / z: 433 (M + + H).
[実施例 38] [6 - [ (3, 3, 3 トリフルォロプロピル)ァミノ]イミダゾ [1 , 2— b]ピリダ ジン 3—ィル]—N— [ [ (2S) 1 メチルピロリジンべンズアミド ギ酸塩  [Example 38] [6-[(3,3,3 trifluoropropyl) amino] imidazo [1,2, -b] pyridazine 3-yl] —N — [[(2S) 1-methylpyrrolidinebenzamide Formate
[0380] [化 134] [0380] [Chemical 134]
Figure imgf000140_0002
Figure imgf000140_0002
[0381] [実施例 28]に記載の 4 [6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル] N [0381] 4 [6 Chloroimidazo [1,2-b] pyridazine 3 yl] N described in [Example 28] N
[ [ (2S)— 1ーメチノレピロリジン 2 ィノレ]メチノレ]ベンズアミド（30mg, 0. 0811 mmol)及び 3, 3, 3 トリフノレ才口プロピノレアミン 塩酸塩（121mg, 0. 81 lmmol) の混合物を、 85。Cで 18· 5日寺間、 100。Cで 13· 5日寺間、さらに 120。Cで 13· 5日寺間攪 拌した。反応混合物を室温に冷却後、分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し、 目的分画を減圧 濃縮して標記化合物（10.5mg, 26%)を得た。 [[(2S) — 1-Methinorepyrrolidine 2-Inole] Metinore] benzamide (30 mg, 0.08111 mmol) and 3, 3, 3 Trifnore-propatile propinoleamine hydrochloride (121 mg, 0.81 lmmol) 85 of a mixture of C at 18 · 5 days Temple, 100. In C 13 · 5 days between the temples, 120 more. C was stirred for 13.5 days. The reaction mixture was cooled to room temperature, purified by preparative HPLC (column: NOMURA Develosil Combi— RP-5, mobile phase: acetonitrile / water / formic acid), the target fraction was concentrated under reduced pressure, and the title compound (10.5 mg, 26 %).
NMR(DMSO-d ) δ :1.54— 1.69 (3Η, m) , 1.81— 1.92(1Η, m) , 2.23(  NMR (DMSO-d) δ: 1.54— 1.69 (3Η, m), 1.81— 1.92 (1Η, m), 2.23 (
6  6
1Η, q, J = 8.6Hz), 2.37(3Η, s) , 2.46— 2.52(1Η, m) , 2.61— 2.74 (2Η , m), 2.97-3.03(1Η, m) , 3. 15— 3.24(1Η, m) , 3.45— 3.52(1Η, m) , 3.57(2Η, q, J = 6.6Hz) , 6.74(1Η, d, J = 9.5Hz) , 7.38(1Η, t, J = 5.6Η ζ), 7.81(1Η, d, J = 9.5Hz), 7.91 (2Η, d, J = 8.5Hz) , 8.02(1Η, s) , 8. 1 7(1Η, s), 8.28 (2Η, d, J = 8.8Hz) , 8.48(1Η, t, J = 6. ΟΗζ) .  1Η, q, J = 8.6Hz), 2.37 (3Η, s), 2.46— 2.52 (1Η, m), 2.61— 2.74 (2Η, m), 2.97-3.03 (1Η, m), 3. 15— 3.24 ( 1Η, m), 3.45— 3.52 (1Η, m), 3.57 (2Η, q, J = 6.6Hz), 6.74 (1Η, d, J = 9.5Hz), 7.38 (1Η, t, J = 5.6Η ζ) , 7.81 (1Η, d, J = 9.5Hz), 7.91 (2Η, d, J = 8.5Hz), 8.02 (1Η, s), 8.1 7 (1Η, s), 8.28 (2Η, d, J = 8.8Hz), 8.48 (1Η, t, J = 6. ΟΗζ).
MS (LC) m/z： 447 (M+ + H) . MS (LC) m / z: 447 (M + + H).
[実施例 39] 4— [6— [[2—（メチルチオ)ェチル]ァミノ]イミダゾ [1, 2— b]ピリダジ ン— 3 ィル] N— [[(2S)— 1—メチルピロリジン— 2 ィル]メチル]ベンズアミド ギ酸塩  [Example 39] 4— [6 — [[2- (Methylthio) ethyl] amino] imidazo [1,2-b] pyridazine-3 yl] N — [[(2S) — 1-methylpyrrolidine-2 Yl] methyl] benzamide formate
[化 135] [Chemical 135]
Figure imgf000141_0001
Figure imgf000141_0001
[実施例 28]に記載の 4 [6 クロロイミダゾ [1, 2— b]ピリダジン 3 ィル] N [[(2S)— 1ーメチノレピロリジン 2 ィノレ]メチノレ]ベンズアミド（30mg, 0.0811 mmol)及び 2 （メチルチオ）ェチルァミン（74mg, 0.81 lmmol)の混合液を、 85 °Cで 18.5時間、 100°Cで 13.5時間、さらに 120°Cで 13.5時間攪拌した。反応混 合物を室温に冷却後、分取 HPLC (カラム： NOMURA Develosil Combi -RP 5、移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮して標記化 合物（12. 5mg, 28%)を得た。 4 [6 Chloroimidazo [1, 2-b] pyridazine 3-yl] N [[(2S)-1-methinorepyrrolidine 2-inore] methinore] benzamide (30 mg, 0.0811 mmol) and [Example 28] A mixture of 2 (methylthio) ethylamine (74 mg, 0.81 lmmol) was stirred at 85 ° C. for 18.5 hours, at 100 ° C. for 13.5 hours, and further at 120 ° C. for 13.5 hours. The reaction mixture is cooled to room temperature and purified by preparative HPLC (column: NOMURA Develosil Combi-RP 5, mobile phase: acetonitrile / water / formic acid). The compound (12.5 mg, 28%) was obtained.
MS (LC) m/z： 425 (M" + H) .  MS (LC) m / z: 425 (M "+ H).
[実施例 40] 4— [6— [ (3—ヒドロキシプロピル）ァミノ]イミダゾ [1 , 2— b]ピリダジン — 3 ィル] N— [ [ (2S)— 1—メチルピロリジン— 2 ィル]メチル]ベンズアミド ギ 酸塩  [Example 40] 4— [6— [(3-Hydroxypropyl) amino] imidazo [1, 2-b] pyridazine — 3 yl] N— [[(2S) — 1-methylpyrrolidine — 2 yl] Methyl] benzamide formate
[0384] [化 136]  [0384] [Chemical 136]
Figure imgf000142_0001
Figure imgf000142_0001
[0385] [実施例 28]に記載の 4 [6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル] N [0385] 4 [6 Chloroimidazo [1,2-b] pyridazine 3 yl] N described in [Example 28] N
[ [ (2S)— 1ーメチノレピロリジン 2 ィノレ]メチノレ]ベンズアミド（30mg, 0. 0811 mmol)及び 3 アミノー 1—プロパノール（60· 9mg, 0. 81 lmmol)の混合液を、 8 5°Cで 18. 5時間、 100°Cで 13. 5時間、さらに 120°Cで 13. 5時間攪拌した。反応混 合物を室温に冷却後、分取 HPLC (カラム： NOMURA Develosil Combi— RP 5、移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮して標記化 合物（13· Omg, 35%)を得た。  [[(2S) — 1-Methinorepyrrolidine 2-Inole] methinore] benzamide (30 mg, 0.08111 mmol) and 3 amino-1-propanol (60 · 9 mg, 0.81 lmmol) were mixed at 85 ° C. The mixture was stirred for 18.5 hours at 100 ° C for 13.5 hours and further at 120 ° C for 13.5 hours. The reaction mixture is cooled to room temperature, purified by preparative HPLC (column: NOMURA Develosil Combi—RP 5, mobile phase: acetonitrile / water / formic acid), and the target fraction is concentrated under reduced pressure to give the title compound (13 · Omg, 35%)
MS (LC) m/z： 409 (M+ + H) . MS (LC) m / z: 409 (M + + H).
[実施例 41] 4 [6— [ (2 メトキシェチル)ァミノ]イミダゾ [1 , 2— b]ピリダジンー3 ィル] N— [ [ ( 2 S )— 1 メチルピロリジン 2—ィル]メチル]ベンズアミド ギ酸 塩  [Example 41] 4 [6 — [(2 methoxyethyl) amino] imidazo [1,2, b] pyridazine-3-yl] N — [[((2S) —1-methylpyrrolidine-2-yl] methyl] benzamide formic acid salt
[0386] [化 137]
Figure imgf000143_0001
[0386] [Chemical 137]
Figure imgf000143_0001
[0387] [実施例 28]に記載の 4 [6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル] N [0387] 4 [6 Chloroimidazo [1, 2—b] pyridazine 3 yl] described in [Example 28] N
[ [ (2S)— 1ーメチノレピロリジン 2 ィノレ]メチノレ]ベンズアミド（30mg, 0. 0811 mmol)及び 2 メトキシェチルァミン（60· 9g, 0. 81 lmmol)の混合液を、 85°Cで 1 8. 5時間、 100°Cで 13. 5時間、さらに 120°Cで 13. 5時間攪拌した。反応混合物を 室温に冷却後、分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移 動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮して標記化合物（1 3. 5mg, 37%)を得た。  [[(2S) — 1-Methinorepyrrolidine 2-Ino] Metinole] benzamide (30 mg, 0.011 mmol) and 2 methoxyethylamine (60 · 9 g, 0.81 lmmol) were mixed at 85 ° C. The mixture was stirred for 18.5 hours at 100 ° C for 13.5 hours and further at 120 ° C for 13.5 hours. The reaction mixture is cooled to room temperature, purified by preparative HPLC (column: NOMURA Develosil Combi—RP-5, mobile phase: acetonitrile / water / formic acid), and the target fraction is concentrated under reduced pressure to give the title compound (1 3. 5 mg, 37%) was obtained.
MS (LC) m/z： 409 (M+ + H) .  MS (LC) m / z: 409 (M + + H).
[実施例 42] 4— [6— [ (テトラヒドロフラン一 2 ィルメチル）ァミノ]イミダゾ [1 , 2— b ]ピリダジン 3—ィル] N— [ [ ( 2 S )— 1 メチルピロリジン 2—ィル]メチル]ベン ズアミド ギ酸塩  [Example 42] 4- [6-[(tetrahydrofuran-2-ylmethyl) amino] imidazo [1,2, -b] pyridazine-3-yl] N-[[((2S)-1-methylpyrrolidine-2-yl] Methyl] benzamide formate
[0388] [化 138] [0388] [Chemical 138]
Figure imgf000143_0002
Figure imgf000143_0002
[0389] [実施例 28]に記載の 4 [6 クロロイミダゾ [1 , 2— b]ピリダジン 3 ィル] N [0389] 4 [6 Chloroimidazo [1, 2—b] pyridazine 3 yl] described in [Example 28] N
[ [ (2S)— 1ーメチノレピロリジン 2 ィノレ]メチノレ]ベンズアミド（30mg, 0. 0811 mmol)及び [(テトラヒドロフランー2 ィノレ）メチル]ァミン（121mg, 0.811mmol) の混合 ί夜を、 85。Cで 18· 5日寺間、 100。Cで 13· 5日寺間、さらに 120。Cで 13· 5日寺間攪 拌した。反応混合物を室温に冷却後、分取 HPLC (カラム： NOMURA Develosil Combi— RP— 5、移動相：ァセトニトリル/水/ギ酸）で精製し及び分画を減圧濃 縮して標記化合物（9.60mg, 25%)を得た。 [[(2S) — 1-Metinolepyrrolidine 2-Ino] Metinore] benzamide (30 mg, 0.0.0811 mmol) and [(tetrahydrofuran-2-inole) methyl] amine (121 mg, 0.811 mmol). C at 18 · 5 days Temple, 100. In C 13 · 5 days between the temples, 120 more. C was stirred for 13.5 days. The reaction mixture was cooled to room temperature, purified by preparative HPLC (column: NOMURA Develosil Combi— RP-5, mobile phase: acetonitrile / water / formic acid), and the fraction was concentrated under reduced pressure to give the title compound (9.60 mg, 25 %).
NMR(DMSO-d ) δ :1.54 1.68 (4Η, m) , 1.74 1.93 (4Η, m) , 1.94  NMR (DMSO-d) δ: 1.54 1.68 (4Η, m), 1.74 1.93 (4Η, m), 1.94
6  6
-2.09(1Η, m), 2.18(1Η, q, J = 8.5Hz) , 2.35(3Η, s) , 2.40— 2.49(1 Η, m), 2.95-3.01(1Η, m) , 3. 13— 3.21(1Η, m) , 3.31— 3.51 (2Η, m ), 3.66(1Η, dd, J=14.0, 7.7Hz) , 3.78— 3.85(1Η, m) , 4.13(1Η, dq, J = 6.8, 6.3Hz), 6.80(1Η, d, J = 9.8Hz) , 7.23(1Η, t, J = 5.6Hz) , 7.7 6(1Η, d, J = 9.8Hz), 7.92 (2Η, d, J = 8.7Hz) , 7.98(1Η, s), 8.19(1Η, s ), 8.29 (2Η, d, J = 8.7Hz) , 8.46(1Η, t, J = 5.7Hz) .  -2.09 (1Η, m), 2.18 (1Η, q, J = 8.5Hz), 2.35 (3Η, s), 2.40— 2.49 (1 Η, m), 2.95-3.01 (1Η, m), 3. 13— 3.21 (1Η, m), 3.31− 3.51 (2Η, m), 3.66 (1Η, dd, J = 14.0, 7.7Hz), 3.78— 3.85 (1Η, m), 4.13 (1Η, dq, J = 6.8, 6.3 Hz), 6.80 (1Η, d, J = 9.8Hz), 7.23 (1Η, t, J = 5.6Hz), 7.7 6 (1Η, d, J = 9.8Hz), 7.92 (2Η, d, J = 8.7Hz) ), 7.98 (1Η, s), 8.19 (1Η, s), 8.29 (2Η, d, J = 8.7Hz), 8.46 (1Η, t, J = 5.7Hz).
MS (LC) m/z： 435 (M+ + H) . MS (LC) m / z: 435 (M + + H).
[実施例 43] 4— [6— [(3 フエノキシプロピル)ァミノ]イミダゾ [1, 2— b]ピリダジン — 3 ィル] N— [[(2S)— 1—メチルピロリジン— 2 ィル]メチル]ベンズアミド ギ 酸塩  [Example 43] 4— [6 — [(3 phenoxypropyl) amino] imidazo [1,2-b] pyridazine—3 yl] N — [[(2S) — 1-methylpyrrolidine—2 yl ] Methyl] benzamide formate
[化 139][Chem 139]
Figure imgf000144_0001
Figure imgf000144_0001
[実施例 28]に記載の 4 [6 クロロイミダゾ [1, 2— b]ピリダジン 3 ィル] N [[(2S)— 1ーメチノレピロリジン 2 ィノレ]メチノレ]ベンズアミド（30mg, 0.0811 mmol)及び 3 フエノキシプロピルアミン（123mg, 0.81 lmmol)の混合液を、 85 °Cで 18.5時間、 100°Cで 13.5時間、さらに 120°Cで 13.5時間攪拌した。反応混 合物を室温に冷却後、分取 HPLC (カラム： NOMURA Develosil Combi— RP 5、移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮して標記化 合物（15.2mg, 35%)を得た。 4 [6 Chloroimidazo [1, 2-b] pyridazine 3-yl] N [[(2S)-1-methinorepyrrolidine 2-inore] methinore] benzamide (30 mg, 0.0811 mmol) and [Example 28] 3 A mixture of phenoxypropylamine (123 mg, 0.81 lmmol) was stirred at 85 ° C. for 18.5 hours, at 100 ° C. for 13.5 hours, and further at 120 ° C. for 13.5 hours. Reaction mixture After cooling the mixture to room temperature, the mixture was purified by preparative HPLC (column: NOMURA Develosil Combi—RP 5, mobile phase: acetonitrile / water / formic acid), and the target fraction was concentrated under reduced pressure to give the title compound (15.2 mg, 35%) was obtained.
MS (LC) m/z： 485(M" + H) . MS (LC) m / z: 485 (M "+ H).
[実施例 44] 4 [6— [[2—（2 チェニル)ェチル]ァミノ]イミダゾ [1, 2— b]ピリダ ジン 3 ィル]—N—[[(2S)—1—メチルピロリジン 2 ィル]メチル]ベンズアミ ド ギ酸塩  [Example 44] 4 [6 — [[2— (2 Cenyl) ethyl] amino] imidazo [1,2-b] pyridazine 3 yl] —N — [[(2S) -1-methylpyrrolidine 2 Ru] methyl] benzamido formate
[化 140] [Chemical 140]
Figure imgf000145_0001
Figure imgf000145_0001
[実施例 28]に記載の 4 [6 クロロイミダゾ [1, 2— b]ピリダジン 3 ィル] N [[(2S)— 1ーメチノレピロリジン 2 ィノレ]メチノレ]ベンズアミド（30mg, 0.0811 mmol)及び [2— (2 チェニル）ェチル]ァミン（103mg, 0.81 lmmol)を力 Qえ、 85 °Cで 18.5時間、 100°Cで 13.5時間、さらに 120°Cで 13.5時間攪拌した。反応混 合物を室温に冷却後、分取 HPLC (カラム： NOMURA Develosil Combi— RP 5、移動相：ァセトニトリル/水/ギ酸)で精製し、 目的分画を減圧濃縮して標記化 合物（10· 4mg, 25%)を得た。 4 [6 Chloroimidazo [1, 2-b] pyridazine 3-yl] N [[(2S)-1-methinorepyrrolidine 2-inore] methinore] benzamide (30 mg, 0.0811 mmol) and [Example 28] [2- (2 Chenyl) ethyl] amine (103 mg, 0.81 lmmol) was vigorously stirred and stirred at 85 ° C. for 18.5 hours, at 100 ° C. for 13.5 hours, and further at 120 ° C. for 13.5 hours. The reaction mixture is cooled to room temperature, purified by preparative HPLC (column: NOMURA Develosil Combi—RP 5, mobile phase: acetonitrile / water / formic acid), and the target fraction is concentrated under reduced pressure to give the title compound (10 · 4mg, 25%)
NMR(DMSO-d ) δ :1.54— 1.71 (3Η, m) , 1.82— 1.92(1Η, m) , 2.22(  NMR (DMSO-d) δ: 1.54— 1.71 (3Η, m), 1.82— 1.92 (1Η, m), 2.22 (
6  6
1Η, dd, J=17.1, 8.3Hz) , 2.37 (3Η, s) , 2.45— 2.55(1Η, m) , 2.97— 3 .03(1Η, m), 3.19(2Η, t, J = 7.1Hz), 3.27— 3.61 (4Η, m) , 6.74(1H, d, J = 9.8Hz), 6.94-6.99 (2H, m) , 7.33— 7.37(2H, m) , 7.78(1H, d, J = 9.8Hz), 7.91 (2H, d, J = 8.4Hz) , 8.00(1H, s) , 8.19(1H, s) , 8.30 ( 2H, d, J = 8.4Hz), 8.46(1H, t, J = 5.6Hz) . MS(LC)m/z:461(M+ + H). 以下に示す実施例 45〜 71の化合物は、上記実施例又は [製造法 1 ]〜 [製造法 A 6]に記載の方法を用いて合成することができる。 1Η, dd, J = 17.1, 8.3Hz), 2.37 (3Η, s), 2.45—2.55 (1Η, m), 2.97—3.03 (1Η, m), 3.19 (2Η, t, J = 7.1Hz) , 3.27— 3.61 (4Η, m), 6.74 (1H, d, J = 9.8Hz), 6.94-6.99 (2H, m), 7.33— 7.37 (2H, m), 7.78 (1H, d, J = 9.8Hz ), 7.91 (2H, d, J = 8.4Hz), 8.00 (1H, s), 8.19 (1H, s), 8.30 (2H, d, J = 8.4Hz), 8.46 (1H, t, J = 5.6Hz ). MS (LC) m / z: 461 (M ++ H). For the compounds of Examples 45 to 71 shown below, use the method described in the above Examples or [Production Method 1] to [Production Method A6]. Can be synthesized.
[表 2] [Table 2]
実施例 化 物名 腿 Example Chemical name Thigh
4— [ 6— [ ( 4—ァゼ 1H-NMR (DMS0-D6) 5 : 1.5 1.7 (IK, m), 1.8- チジン— 1 —ィル— 4一 1.9 (2H, m) , 2.0-2.2 (5H, m), 2.9-3.1 (2H， ォキソプチル） ァミノ] m), 3, 2-3.3 (4H, m) , 3.4- 3.5 (1H, m), 3.8 イミダゾ [ 1 ， 2 - b] (2Η, t, J = 7.8 ΗΪ), 4. t (2H, t, J = 7.6 Hz), ピリダジン 3 —ィル] 5.2 (111, dt, J = 55.5, 3.2 Hz), 6.7 (1H, (し J 4— [6— [(4-Aze 1H-NMR (DMS0-D6) 5: 1.5 1.7 (IK, m), 1.8-Tidine — 1 — Fil— 4 1 1.9 (2H, m), 2.0-2.2 (5H, m), 2.9-3.1 (2H, oxoptyl) amino] m), 3, 2-3.3 (4H, m), 3.4- 3.5 (1H, m), 3.8 Imidazo [1, 2-b] (2Η , t, J = 7.8 ΗΪ), 4. t (2H, t, J = 7.6 Hz), pyridazine 3 —yl] 5.2 (111, dt, J = 55.5, 3.2 Hz), 6.7 (1H, (
45 45
— 2—フルオロー N— [ = 9. B Hz), 7.2 (1H, t, J = 5.3 Hz) , 7.7 (1H, [ ( 2 S , 4 R) — 4— t， J = 8.3 Hz), 7.8 (1H, d, J = 9.6 Hz), 8.1 フルォロピロリジン一 2 (1H, s), S. I (IK, (1(1, J = 8.3, 1.4 Hz), 8.2 —ィル] メチル] ベンズ (1H, dd, J = 9.2, 5.5 Hz) 8.3 (111, lid, J = アミ ド 13.3, 1.4 Hz) .  — 2—Fluoro-N— [= 9. B Hz), 7.2 (1H, t, J = 5.3 Hz), 7.7 (1H, [(2 S, 4 R) — 4— t, J = 8.3 Hz), 7.8 (1H, d, J = 9.6 Hz), 8.1 Fluoropyrrolidine 2 (1H, s), S. I (IK, (1 (1, J = 8.3, 1.4 Hz), 8.2 —yl] methyl] Benz (1H, dd, J = 9.2, 5.5 Hz) 8.3 (111, lid, J = amide 13.3, 1.4 Hz).
2—フルォロ— 4一 [ 6 1H-NMR (DMS0-DS) δ ： I.5 -1. 9 (SIし m), 2.0- 一 [ ( 4—フルォロプチ 2.1 (1H, m), 2.9-3.0 (2H, m) ， 3.2 3. Ά (2H, ル） ァミノ] ィミダゾ [ H πし S 3 -ι：)， 3.3 3.4 (2Η, m) , 3.4- 3.5 (lli, m), 4.4-4.5 1， 2 - b] ピリダジン (1 H HH) 9 >67, m), 4.6 (tH, t, J = 6.0 Hz), 5.2 (IK, d, I 一 3—ィル] — N— [ [ J = 55.5 Hz), 6.8 (1H, ύ, J = 9.6 Hz) , 7.1 ( 2 S , 4 ) 4ーフ (1H, s), 7.7 (1H, tl, J = 7. S Hz), 7.7 (1H, ri, ルォロピロリジン一 2 — J = 9.6 Hz), 7.9-8.0 (1H， ra) , 8.0 (1H, s), ィル] メチル〗 ベンズァ 8.1 (III, d, J = 7.8 Hz) , 8.2 ( , d, J = 12. ¾ ≤ ド Hz).  2—Fluoro—4 1 [6 1H-NMR (DMS0-DS) δ: I.5 -1. 9 (SI m), 2.0- 1 [(4—Fluoropetit 2.1 (1H, m), 2.9-3.0 ( 2H, m), 3.2 3. Ά (2H, Le) Amino] imidazo [H π S 3 -ι :), 3.3 3.4 (2 Η, m), 3.4- 3.5 (lli, m), 4.4-4.5 1, 2-b] pyridazine (1 H HH) 9> 67, m), 4.6 (tH, t, J = 6.0 Hz), 5.2 (IK, d, I 1 3-yl] — N— [[J = 55.5 Hz), 6.8 (1H, ύ, J = 9.6 Hz), 7.1 (2 S, 4) 4-fu (1H, s), 7.7 (1H, tl, J = 7. S Hz), 7.7 (1H, ri , Pyrrolopyrrolidine 1 — J = 9.6 Hz), 7.9-8.0 (1H, ra), 8.0 (1H, s), Il] Methyl〗 Benza 8.1 (III, d, J = 7.8 Hz), 8.2 (, d, J = 12. ¾ ≤ de Hz).
-隱 (DMS0-DB) δ 1.6-1.7 (1H, m) , 1.8- -隱 (DMS0-DB) δ 1.6-1.7 (1H, m), 1.8-
4 - [ 6 - [ ( 4—フル 4-[6-[(4—Full
(4H, m), 2.0-2.1 (ll!, m) , 2.9-3.2 H, ォロブチル） ァミノ ] ィ  (4H, m), 2.0-2.1 (ll !, m), 2.9-3.2 H, allobutyl) amino]
3.3-3.4 (4H， m), 3.5-3.5 (1H, m), 4.5-4.5 ミダゾ [ 1 , 2— b ] ピ  3.3-3.4 (4H, m), 3.5-3.5 (1H, m), 4.5-4.5 Midazo [1, 2-b]
m), 4.6 (1H， t， J = 6.0 Hz), 5.3 (1H, りダジン— 3—ィル] ―  m), 4.6 (1H, t, J = 6.0 Hz), 5.3 (1H, Ridadine-3-yl]-
47 J - 5S.4， 4.4 Hz), 6. S (IH, ύ, J - 9.6 N - [ [ ( 2 S , 4 R)  47 J-5S.4, 4.4 Hz), 6. S (IH, ύ, J-9.6 N-[[(2 S, 4 R)
7.2 (1H, t， J = 5.5 Hz), 7.8 (1H, d, J = — 4—フル才ロピロリジ  7.2 (1H, t, J = 5.5 Hz), 7.8 (1H, d, J = — 4—full-year-old lopyrroliz
Hz), S.0 (2H, d, J = 8.7 Hz), 8.0 (HI, ンー 2—ィル] メチル]  Hz), S.0 (2H, d, J = 8.7 Hz), 8.0 (HI, 2-yl) methyl]
8.3 (2H, d, J = 8. Ί Hz), 8.5 (1H, L J = ペンズアミ ド  8.3 (2H, d, J = 8. Ί Hz), 8.5 (1H, L J = penzamide
Hz).  Hz).
1H-NMR (DMS0-D6) 6 : 1.5 -1.7 (1H, m), 2.0- 1H-NMR (DMS0-D6) 6: 1.5 -1.7 (1H, m), 2.0-
2 フルオロー 4 [ 6 2 Fluoro 4 [6
2.1 (3H, ra), 2. Ί-Ί.9 (1H, ni), 2.9-3.1 (2H, 一 [ ( 3—フルォ口プロ  2.1 (3H, ra), 2. Ί-Ί.9 (1H, ni), 2.9-3.1 (2H, One [(3--Fluoropro
m), 3.2-3.3 (2H, m) , 3.4- 3.5 (3H, m), 4.5 ピル） ァミノ] イミダゾ  m), 3.2-3.3 (2H, m), 3.4-3.5 (3H, m), 4.5 pills) Amino] imidazo
(ΙΗ, " I = Γι.7 ΙΙζ), 4.7 (1H, t, J = fi.O Hz) , (ΙΗ, "I = Γι.7 ΙΙζ), 4.7 (1H, t, J = fi.O Hz),
[ 1 , 2 - b] ピリダジ [1, 2-b] pyridazi
5.2 (1Η, dt, J = SB. fi, 1.9 Hz), fi.8 (IK, d, J I ンー 3—ィル] — N— [  5.2 (1Η, dt, J = SB. Fi, 1.9 Hz), fi.8 (IK, d, J I N 3 -il] — N— [
= 9.6 Hz), 7.3 (tH, t, J = 5.3 Hz), 7. T (1H, = 9.6 Hz), 7.3 (tH, t, J = 5.3 Hz), 7.T (1H,
[ ( 2 S , 4 R) - 4 - i， J = 8.0 Hz), 7.8 (ill, (1, J = 9.6 l[z)， 8.1 フル才ロピロリジン— 2 [(2 S, 4 R)-4-i, J = 8.0 Hz), 7.8 (ill, (1, J = 9.6 l [z), 8.1 Full-year-old ropyrrolidine-2
(1H, dd, J = 7.8, 1.8 Hz) , S.1 (1H, s), 8.2 —ィル] メチル] ベンズ  (1H, dd, J = 7.8, 1.8 Hz), S.1 (1H, s), 8.2 —methyl] methyl] benz
(111, ci, J = 4.9 Hz), 8.3 (1H, dd, J - I' 3, アミ ド  (111, ci, J = 4.9 Hz), 8.3 (1H, dd, J-I '3, Amid
t.4 Hz).  t.4 Hz).
2—フルオロー N— [ [ 1H-NMR (DMSO-D6) 5 : 1.5 1.7 (1H, m), 1.9- ( 2 S， 4 R) — 4—フ 2.0 (3H, ra), 2.1 (3H, s), 2.6 (2H, t, J = 7.3 ルォロピロリジン _ 2 _ Hz), 2.9-3. I (2H, m) , 3.2 3.3 (2H, in), 3.4- ィル] メチル] 4一 （ 3.5 (4H, ra)， 5.2 (1H, dt, J = 55.6, 4.0 Hz), I 6 - [ [ 3 - (メチルチ 6.8 (1H, d, J = 10.5 Hz), 7.3 (1H, t, J = 5.3 ォ〉 プロピル] ァミノ] Hz), T.7 (1H, t, J = 8.3 Hz), 7.8 (1H, d, J = イミダゾ [し 2 - b] 10.1 Hz), 8.1 (1H, s), 8 1 (1H, dd, ] = 8.3, ピリダジン— 3 —ィル） 1.4 Hz), 8.2 (1H, q, J = 5.0 Hz), 8.3 (1H, ベンズアミ ド dd, J = 12.8, 1.4 Hz) . 2 —フルォ Π— N— [ [ 1H R (DMS0-D6) δ： 1.5- 7 (IH, m) , 2.0-2-Fluoro-N— [[1H-NMR (DMSO-D6) 5: 1.5 1.7 (1H, m), 1.9- (2 S, 4 R) — 4-F 2.0 (3H, ra), 2.1 (3H, s ), 2.6 (2H, t, J = 7.3 pyrrolopyrrolidine _ 2 _ Hz), 2.9-3. I (2H, m), 3.2 3.3 (2H, in), 3.4-yl] methyl] 4 1 (3.5 (4H , ra), 5.2 (1H, dt, J = 55.6, 4.0 Hz), I 6-[[3-(methylthiol 6.8 (1H, d, J = 10.5 Hz), 7.3 (1H, t, J = 5.3 Propyl] amino] Hz), T.7 (1H, t, J = 8.3 Hz), 7.8 (1H, d, J = imidazo [2-b] 10.1 Hz), 8.1 (1H, s), 8 1 ( 1H, dd,] = 8.3, pyridazine— 3 —yl) 1.4 Hz), 8.2 (1H, q, J = 5.0 Hz), 8.3 (1H, benzamide dd, J = 12.8, 1.4 Hz). 2 —Fluo Π— N— [[1H R (DMS0-D6) δ: 1.5-7 (IH, m), 2.0-
( 2 S， 4 R) 一 4ーフ 2.1 {3H, m) , 2.6-2.8 (1H， IT) , 2.9-3.1 (2H, ルォ L ピロリジン一 2— ni), 3,0 (3H, s)， 3.2-3.3 (4H， ni)， 3.4— 3.5 ィル] メテル] — 4 ΐ (3H, m)， 5. (IH, dt, J = 55.5' 4.1 Hz) , 6.8(2 S, 4 R) 1 4-fu 2.1 (3H, m), 2.6-2.8 (1H, IT), 2.9-3.1 (2H, Luo L pyrrolidine 1 2-ni), 3,0 (3H, s) , 3.2-3.3 (4H, ni), 3.4—3.5 il] Meter] — 4 ΐ (3H, m), 5. (IH, dt, J = 55.5 '4.1 Hz), 6.8
6 - [ [ 3 - (メチルス (IH, d, J - 9.6 Hz), Ί, 3 (IH, t, J = a.3 Hz), ルホニル） プロピル] ァ 7. S (IH, t, i 二 8.0 Hz), 7.8 (IIし d， J - 9.6 ミノ] イミダゾ [ 1， 2 .1 (HI, s); 8.1 (IH, dd, J = 8.3， L.8 - b] ピリダジン— 3— Hz): (Uし m)， 8.2 (IH, dd, J - 12.8, ィル） ペンズアミ ド 1.8 Hz). 6-[[3-(Methyls (IH, d, J-9.6 Hz), Ί, 3 (IH, t, J = a.3 Hz), sulfonyl) propyl] a 7. S (IH, t, i 8.0 Hz), 7.8 (II and d, J-9.6 Mino] imidazo [1, 2.1 (HI, s) ; 8.1 (IH, dd, J = 8.3, L.8-b] pyridazine— 3—Hz) : (U m), 8.2 (IH, dd, J-12.8, Yil) pensamide 1.8 Hz).
N— [ [ ( 2 S， 4 R ) 1H-NMR (DMS0-D6) ί.5-1.7 (IH, m)， し 9一 _ 4—フルォロピロリジ .1 (3H， m), 2.1 s)， 2.6 f, j = 7.3 ン— 2 —ィル] メチル] Hz), 2.9-3.1 (IH, m)， 3.2-3.5 C6HT ni) T 5.2 — 4— ( ό一 [ [ 3— ( (IH, ill, J - b. &, 4.1 Hz), 6.7 (IH, tl， J -N— [[(2 S, 4 R) 1H-NMR (DMS0-D6) ί.5-1.7 (IH, m), 9 _ 4—Fluoropyrrolid.1 (3H, m), 2.1 s), 2.6 f, j = 7.3 N—2 —Mil] Hz), 2.9-3.1 (IH, m), 3.2-3.5 C6H T ni) T 5.2 — 4— (ό 一 [[3— ((IH, ill , J-b. &, 4.1 Hz), 6.7 (IH, tl, J-
51 51
メチルチオ） プロピル] 10.1 Hz), 7.2 (IH, t, J - 5.3 Hz)， 7.8 (1H， ァミノ] イミダゾ [ 1， (J, J - 9.6 Hz), 8.0 (2H, fl, J - 8.7 Hz)， 8.0 2 - b] ピリダジン— 3 (IH, s)， 8, Η (2H, d， J = ¾.7 Wz), 8.5 (1H， t， 一ィル） ベンズアミ ド J = 5.7 Hz) .  Methylthio) propyl] 10.1 Hz), 7.2 (IH, t, J-5.3 Hz), 7.8 (1H, amino) imidazo [1, (J, J-9.6 Hz), 8.0 (2H, fl, J-8.7 Hz) , 8.0 2-b] Pyridazine-3 (IH, s), 8, Η (2H, d, J = ¾.7 Wz), 8.5 (1H, t, Iil) benzamide J = 5.7 Hz).
2—フルォロ一 N— [ [ 1H-N R (DMS0-D6) δ ：  2—Fluoro N— [[1H-N R (DMS0-D6) δ:
( 2 S , 4 ) - 4—フ 2.1 (Η1， π ， 2.1 (3Η,  (2 S, 4)-4—F 2.1 (Η1, π, 2.1 (3Η,
ルォロピ リジン一 2 - Hz), 2.9-3.1 H， π ,  Uropyridine 1-2 Hz), 2.9-3.1 H, π,
ィル] メチル] 一 4一 （ 3.5 (111, m)， 3.5-3.6 m)  Yil] Methyl] One 41 (3.5 (111, m), 3.5-3.6 m)
52 6 - [ [ ^ - (メチルチ = 55.5, 4.4 Ιίζ), 6. S d, Elz ォ） エヂル] ァミノ ] ィ ClH, s)， 7.7 (IH, d, .7  52 6-[[^-(Methylthio = 55.5, 4.4 ζίζ), 6. S d, Elz o) edyl] Amino] Cl ClH, s), 7.7 (IH, d, .7
ミダゾ [ 1， 2 - b] ピ J = 1.8 Hz), . -7- m)  Midazo [1, 2-b] pi J = 1.8 Hz),. -7- m)
リダジン— 3—ィル） ベ 8.0 (IH, thlf J 二 Ridazine—3-yl) Be 8.0 (IH, thl f J
ンズアミ ド = 13丄 1.6 Hz).  (Nsamide = 13 丄 1.6 Hz).
4一 [ 6 - [ ( 5 _フル 1H-NMR (DMS0-D6) δ ： 1. (7Η, m) , 2.0- ォロペンチル） ァミノ] 2.1 (111, tn)， 2.9-3.2 C3H, m) , 3.2-^4 ( H, イミダゾ [ 1， 2— b] ni), (1H, m) , 4.4 (1H, t， J = 6.0 Hz) ; ピリダジン一 3—ィル] 4. r {1H, t， J : fi.2 its)， &.2 (1H, dt， J = ί,3 4 1 [6-[(5 _ full 1H-NMR (DMS0-D6) δ: 1. (7Η, m), 2.0- olopentyl) amino] 2.1 (111, tn), 2.9-3.2 C3H, m), 3.2 -^ 4 (H, imidazo [1, 2—b] ni), (1H, m), 4.4 (1H, t, J = 6.0 Hz) ; pyridazine one 3-yl] 4. r {1H, t, J: fi.2 its), & .2 (1H, dt, J = ί, 3
— N - [ [ ( 2 S， 4 R 5? .7 Hz), 6.7 (1H, t], 】 = 9.6 Hz) , 6.9— N-[[(2 S, 4 R 5 ? .7 Hz), 6.7 (1H, t],] = 9.6 Hz), 6.9
) 一 4一フルォ nピロリ Gil, br s) , 7. (1H, (1， J = 9.fi i【z)， 7.9 (2K. ジン一 2—ィル] メチル d， ] = 8.7 Mz)f 7. (1H， s)， 8.2 (!H, br s) , ] ベンズアミ ド ¾.3 (2H， d， J = 8.7 Hz). ) 4-1Fluoro pylori Gil, br s), 7. (1H, (1, J = 9.fi i [z), 7.9 (2K. Gin-2-yl] methyl d,] = 8.7 Mz) f 7. (1H, s), 8.2 (! H, br s),] Benzamide ¾.3 (2H, d, J = 8.7 Hz).
2 —フルォロ一 4— 1： 6  2 —Fluoro 4— 1: 6
Uト靈 {DMS0-D6) (5 ： 1. 8 (7Hf m)， 2.0- — [ ( 5—フルォ Πペン U 靈 {DMS0-D6) (5: 1. 8 (7H f m), 2.0- — [(5—Fluoro pen
'L t (IK, m), 2.9-S. I (3H, m) , 3.2-3.4 (4iし チル） ァミノ ] イミダゾ  'L t (IK, m), 2.9-S. I (3H, m), 3.2-3.4 (4i and chill) amino] imidazo
m)， 3,4-3.5 (1H, in)， 4.4 (ill, t, J - 6.0 Hz) m), 3,4-3.5 (1H, in), 4.4 (ill, t, J-6.0 Hz)
[ 1， 2 ~ J ビリダジ [1, 2 ~ J Viridaji
4.5 (1H, t, J = 6.2 Hz)、 2 (1H, dtt J -4.5 (1H, t, J = 6.2 Hz), 2 (1H, dt t J-
54 ン— 3 ィル] — N— [ 54-3 il] — N— [
55. , 4.6 Hs)， 8 ClH, d, J = 10.1 Hz)， 7.0 55, 4.6 Hs), 8 ClH, d, J = 10.1 Hz), 7.0
[ { 2 S, 4 R) 4— [{2 S, 4 R) 4—
(1H, br s)， 7.7-7.8 (2H, m) , 7.9 (1H, br s) , フル才ロピロリジン— 2  (1H, br s), 7.7-7.8 (2H, m), 7.9 (1H, br s), Full-year-old ropyrrolidine-2
8.0 (1H， s) , B.O ClH, (Id, 〗 = 8.3, 1.8 Hz), 一ィル] メチル〗 ペンズ  8.0 (1H, s), B.O ClH, (Id,〗 = 8.3, 1.8 Hz), Iil] Methyl ペ ン Pens
8.2 (1H， dd, J = 13.3， 1.4 Hz).  8.2 (1H, dd, J = 13.3, 1.4 Hz).
アミド  Amide
2 -フル才ロ 4一 [ 6  2-Full age 4 4 [6
1H-NMR (DMS0-D6) d 1.4-1.5 (4H， m), 1.6- - [ ( 6—フルォ口へキ  1H-NMR (DMS0-D6) d 1.4-1.5 (4H, m), 1.6--[(6-Fluoro
I.7 (5K, m)， 2.0-2.1 (IH, m)， 2.9-3.1 (3H, シル） ァミノ ] イミダゾ  I.7 (5K, m), 2.0-2.1 (IH, m), 2.9-3.1 (3H, Syl) Amino] Imidazo
m)， 3.2-3.4 C4H, m)， 3.4-3.5 (IH, m), 4.4 m), 3.2-3.4 C4H, m), 3.4-3.5 (IH, m), 4.4
[ 1， - b] ピリダジ [1, -b] pyridazi
CIH, し J - 6.0 Hz), 4.5 (1H， t， J ^ 6.2 Hz) , ン 3 —ィル] — N— [  CIH, then J-6.0 Hz), 4.5 (1H, t, J ^ 6.2 Hz), N 3 —il] — N— [
5.2 (IH, dt, J - 5 5, 5.0 Wz) 6.7 (IK, d ] ί ( 2 S> 4 R) 一 4—  5.2 (IH, dt, J-5 5, 5.0 Wz) 6.7 (IK, d] ί (2 S> 4 R) 1 4—
= 9.6 Hz), 7.0 ClH, br s)f 7.7 7.8 (2H, ci), フルォロピロリジン一 2 = 9.6 Hz), 7.0 ClH, br s) f 7.7 7.8 (2H, ci), fluoropyrrolidine 1
T.9 ClH, br s), 8,0 ClH, s), 8 0 (IH, dd, J - —ィル] メチル] ベンズ  T.9 ClH, br s), 8,0 ClH, s), 8 0 (IH, dd, J-—yl] methyl] benz
8.3, 1.4 Hz), 8. (111, dfi, J = 13.3, 1.4 Hz). アミ ド 4一 [ 6 - [ ( 6—フル 1H-NMR (DMS0-D6) δ 1.4-1.7 (9H, ), 2.0- 才口へキシル〉 ァミノ:！ 2.1 C1H, m), 2.9-3.2 (3H, m), 3.2-3.4 (4H， イミダゾ [ 1， 2— b] m)， 3.4-3.5 (ίΗ, in), '1,4 C1H, J ， 6.0 Hz), ピリダジン一 3 —ィル] 4.5 Π1Ι, t, J - 6.2 Hs), 5.2 (1H， dt, I =8.3, 1.4 Hz), 8. (111, dfi, J = 13.3, 1.4 Hz). 4 1 [6-[(6-Full 1H-NMR (DMS0-D6) δ 1.4-1.7 (9H,), 2.0-year-old hexyl) Amino :! 2.1 C1H, m), 2.9-3.2 (3H, m ), 3.2-3.4 (4H, imidazo [1, 2—b] m), 3.4-3.5 (ίΗ, in), '1,4 C1H, J, 6.0 Hz), pyridazine one 3—yl] 4.5 Π1Ι, t, J-6.2 Hs), 5.2 (1H, dt, I =
56 56
-N- [ [ ( 2 S, 4 R 55.9, 4.6 Hz), 6.7 (Hi, d, J = 9. G HzJ, 6.9 ) 一 4一フルォロピロリ (III, br s), 7.7 (1H， d, J - 9.6 Hz), 7.9-7.9 ジン 2—ィル] メチル (3H, m), S.2 (iH, br s) S.3 d, J - 8.3 ] ベンズアミ ド Hz).  -N- [[(2 S, 4 R 55.9, 4.6 Hz), 6.7 (Hi, d, J = 9. G HzJ, 6.9) 4-1 Fluoropyrrolyl (III, br s), 7.7 (1H, d, J -9.6 Hz), 7.9-7.9 Gin 2-yl] methyl (3H, m), S.2 (iH, br s) S.3 d, J-8.3] benzamide Hz).
N - ( ( R ) - 6 , 6 - IH-NM (D S0-D6) δ ： I. I (3H， s)， 1.2 (3H, ジメチルモルホリン一 3 s), 2. [ (3H, $), 2. r~'L 8 (1H, m) , 2.fi (211， d， ィルメチル） 4一 [ J = 11.9 ilz), 2.7-2.8 ( H, m) , 2 (3H, t, I 6 - ( 2—メチルスルフ = fi.O Hz), — S (3H, m)， 6.8 (IH, d, J =N-((R)-6, 6-IH-NM (D S0-D6) δ: I. I (3H, s), 1.2 (3H, dimethylmorpholine 1 s), 2. [(3H, $) , 2. r ~ 'L 8 (1H, m), 2.fi (211, d, ilmethyl) 4 1 [J = 11.9 ilz), 2.7-2.8 (H, m), 2 (3H, t, I 6 -(2—Methylsulf = fi.O Hz), — S (3H, m), 6.8 (IH, d, J =
57 57
ァニルェチルァミノ） ィ 9.6 Hz), 7.3 (1H, t, J = 5.7 Hz), 7.8 (tH, (\, ミダゾ [ ] ， 2 — b] ピ J = 9.6 IIz), 7.9 d, I = 8.7 Hz), 8.0 リダジン— 3—ィル] ベ (IH, s), 8.3 (2H, d, J ^ ¾.3 Hz), S. i> (IH, t， ンズァミ ド J - 5.7 Hz).  Anilethylamino) 9.6 Hz), 7.3 (1H, t, J = 5.7 Hz), 7.8 (tH, (\, Midazo [], 2 — b] Pi J = 9.6 IIz), 7.9 d, I = 8.7 Hz), 8.0 Lidazine— 3—yl] Be (IH, s), 8.3 (2H, d, J ^ ¾.3 Hz), S. i> (IH, t, Nzamide J-5.7 Hz) .
lli- R (DMS0-D6) ό ： 1. t ( t t， J = 7.1 - ( ( ) - 6 , 6 -lli- R (DMS0-D6) ό: 1. t ( t t, J = 7.1-(()-6, 6-
Hz), 1.2 (3H, t, J 二 7, 3 Hz), ].2 H， s)， ジメチルモルホリ 3 Hz), 1.2 (3H, t, J 2 7, 3 Hz),] .2 H, s), dimethylmorpholine 3
2.6 (3H， dd， J 11.1 ， 7 .3 IEz)， 2 .6-2. 8 (IH, 一ィルメチル） 一 4一 [  2.6 (3H, dd, J 11.1, 7.3 IEz), 2.6-2.8 (IH, monomethyl)
01)， 2.8 (21し t, J = 7 , 1 Hz), 3.2 (2H， (], J = 6 - ( 2ーェチルスルフ  01), 2.8 (21 and t, J = 7, 1 Hz), 3.2 (2H, (], J = 6-(2-etylsulfur
,「,8 4.6 Kz), 2 C2H, t, J = S- 1 Hz)， 3.4- -3, 5 ァニルェチルアミノ） ィ  , ", 8 4.6 Kz), 2 C2H, t, J = S-1 Hz), 3.4- -3, 5 aniethylethyl)
(4H， )， 6.7 CIJI, d， 3 - 9.8 Hz), Ί.'λ CIH, ΐ, ミダゾ [ 1， 2— b] ピ  (4H,), 6.7 CIJI, d, 3-9.8 Hz), Ί.'λ CIH, ΐ, Midazo [1, 2—b]
J = 5.6 Hz), 7.S (IH, (1, J - 9.5 Hz), 7.9 リダジン— 3 —ィル] ベ  J = 5.6 Hz), 7.S (IH, (1, J-9.5 Hz), 7.9 Ridazine—3
(2H, d, J ： 8.5 Hz), 8.0 (IH, s), 8, 3- -8.3 ンズァミ ド  (2H, d, J: 8.5 Hz), 8.0 (IH, s), 8, 3- -8.3
(2H, m), S.5 (IH, t， J - S.7 Ifz) .  (2H, m), S.5 (IH, t, J-S.7 Ifz).
1H -醒 ( nCU) (5 ： し: ί H, し J - 8.3 Hz), 1.6-1.7 (1H, π ， 2.2-2.3 (IH, ra), 2.6 (211, a 1H -Awakening (nCU) (5: Shi: ί H, Shi J-8.3 Hz), 1.6-1.7 (1H, π, 2.2-2.3 (IH, ra), 2.6 (211, a
4 _ ( 6 [ [ 2— (ェ 4 _ (6 [[2— (
J U \iz) 2. (2H, t , J = S H2) , 2.9 チルチオ） ェチル〗 ァミ  J U \ iz) 2. (2H, t, J = S H2), 2.9 Tilthio)
(IH, dd, J = 13.5, 3.1 Hz), 3.0 (IH, dd, J = ノ ] イミダゾ [ 1 , 2—  (IH, dd, J = 13.5, 3.1 Hz), 3.0 (IH, dd, J = No] imidazo [1, 2—
ΐ:ΐ.7， 3.2 Hz), 3.2-3.3 (211, m), 3.6 (2H， q， b ] ピリダジン— 3—ィ  ΐ: ΐ.7, 3.2 Hz), 3.2-3.3 (211, m), 3.6 (2H, q, b] pyridazine— 3—
Γι9 = I Hz), 3.7-3.7 (2H， in), 5. I (IH, i, J 二 ル） — N— [ [ (2 S，  Γι9 = I Hz), 3.7-3.7 (2H, in), 5. I (IH, i, J Nil) — N— [[(2 S,
Γ,. Γ. Hz), [.2 (1HT tit, J - 54. ΰ， %.6 Hz), 6.5 4 R) 1 フルォロピ Γ ,. Γ. Hz), [.2 (1H T tit, J-54. ΰ,% .6 Hz), 6.5 4 R) 1 Fluoropi
(1H， d, J = 10.5 Hz), 7.0 (IH, 【， J = Γ>.6 口リジン一 2 —ィル] メ  (1H, d, J = 10.5 Hz), 7.0 (IH, 【, J = Γ> .6
Hz), 7.7 (IH, d, J = 9.5 Kz)， 7.9 {IH, s) , チル] ベンズァミ ド  Hz), 7.7 (IH, d, J = 9.5 Kz), 7.9 (IH, s), chill] benzamide
7.9 d, ) - 8, Γ> H2) , 8.2 (211, ϋ7 J - 8.57.9 d,)-8, Γ> H2), 8.2 (211, ϋ 7 J-8.5
Hz). Hz).
1H-NMR (DMSO- DS) δ ： 2.0- (Itし m), 2. !- 1H-NMR (DMSO-DS) δ: 2.0- (It m), 2.!-
2 一フルォロ _ N— [ [ 2 Fluoro _ N— [[
2, 2 (IK, m lL 1 (3H, s)， (2H, " J = 6.9 ( 2 R , 3 S ) _ 3—メ 2, 2 (IK, m l L 1 (3H, s), (2H, "J = 6.9 (2 R, 3 S) _ 3- menu
Hz), 3.4-¾.3 (21[， m). 3.3 s)， 3.6 C2H, トキシピ Πリジン一 2—  Hz), 3.4-¾.3 (21 [, m). 3.3 s), 3.6 C2H, Toxipi lysine 1—
t， J = 7.1 Hz), 3.6 (2H, t, J = 6.2 Hz), 3.7 ィル] メチル] 一 4— (  t, J = 7.1 Hz), 3.6 (2H, t, J = 6.2 Hz), 3.7 yl] methyl]
I ClH, r s), 4.0-4.0 (1H， n ， 7.1 (IK, d, J = 6 - [ [ 2 - (メチルチ  I ClH, r s), 4.0-4.0 (1H, n, 7.1 (IK, d, J = 6-[[2-(Methylthio
8.7 IIz), 7.9 (IH, t, J - 8.0 Hz)， 7.9 (U[, d, ォ） ェチル] ァミノ] ィ  8.7 IIz), 7.9 (IH, t, J-8.0 Hz), 7.9 (U [, d, o) ethyl] amino]
J = 9.9 llz) , 8.1 (IH, dd J = 8.3, 1.4 Hz), ミダゾ [ 1， 2 — b〗 ビ  J = 9.9 llz), 8.1 (IH, dd J = 8.3, 1.4 Hz), midazo [1, 2 — b〗 bi
8.2 (IH, iitl, J - 12. R, 1 fi H7), fi.3 (IH, s), リダジン— 3—ィル） ベ  8.2 (IH, iitl, J-12. R, 1 fi H7), fi.3 (IH, s), Ridazine—3-yl)
8.6-8. fi (1H， m), 9.3 (IH br s)， 9.G (IH, br ンズァミ ド  8.6-8. Fi (1H, m), 9.3 (IH br s), 9.G (IH, br namide)
s).  s).
1H-N R (DMS0-D6) δ ： 1.7-1.9 (4H, m), 2.0- 1H-N R (DMS0-D6) δ: 1.7-1.9 (4H, m), 2.0-
2 -フルオロー 4一 [ 6 2-Fluoro-4 1 [6
2.1 (IH, m), 2. ί-2.2 (ΙΗ' m)， 3.3 (3H， s), — [ ( 4—フルォロブチ  2.1 (IH, m), 2. ί-2.2 (ΙΗ 'm), 3.3 (3H, s), — [(4—Fluorobuti
i.3-3.4 (4H， m), 3.6 (2H， t, J = 6.2 Hz), ル） ァミノ ] イミダゾ [  i.3-3.4 (4H, m), 3.6 (2H, t, J = 6.2 Hz), Lu) Amino] Imidazo [
3.7- 8 (IH， in), 4.0-4.0 CIH, ffl)， 4.4 (1H， し 1， 2 - ] ピリダジン  3.7-8 (IH, in), 4.0-4.0 CIH, ffl), 4.4 (1H, SH1, 2--) pyridazine
I = 5.7 H2) , 4.6 (111, J = 6.0 Hz), 7. I I ― 3 -ィル] — N - [ [  I = 5.7 H2), 4.6 (111, J = 6.0 Hz), 7. I I ― 3 -yl] — N-[[
(IH, d， J = 9.6 Hs)， 7.9 ίΙΗ i, J = 8.3 Hz), ( 2 R, 3 S) 一 3 -メ  (IH, d, J = 9.6 Hs), 7.9 ίΙΗ i, J = 8.3 Hz), (2 R, 3 S)
1, 9 (IH, d， J = 9.6 Wz), 8. t {IK, dd, ] - 卜キシピロリジン— 2 —  1, 9 (IH, d, J = 9.6 Wz), 8. t {IK, dd,]-卜 xypyrrolidine — 2 —
8.0, 1-6 Hz), 8.2 (IH, dd, J = 12.8, 1.4 Hz), ィル] メチル] ペンズァ  8.0, 1-6 Hz), 8.2 (IH, dd, J = 12.8, 1.4 Hz), IL] Methyl]
8.3 (IH, s)， 8.6-8. β (IK, m) 9.3 (IH, br s)， ミ ド  8.3 (IH, s), 8.6-8. Β (IK, m) 9.3 (IH, br s), mid
9.6 (1H， br s) . 2 フルォ U— 4— [ 6 9.6 (1H, br s). 2 Fluo U— 4— [6
1H-NMR (DMS0-D6) 1.7-2.2 (6H 3.0 一 [ ( 4—フルォロブチ  1H-NMR (DMS0-D6) 1.7-2.2 (6H 3.0 One [(4-Fluorobuty
〔2 s)， 3.3 (2H, 3.4 (2H, t， J - 6.4 ル） ァミノ] イミダゾ [ [2 s], 3.3 (2H, 3.4 (2H, t, J-6.4 Le) amino] imidazo [
)， 3.5-4.0 (81し 4.4 (IH, t， J - 5.7 1 , 2 - b ] ピリダジン  ), 3.5-4.0 (81 and 4.4 (IH, t, J-5.7 1, 2-b] pyridazine
Ηζ)， 4.5 CIH, -:， J 6.0 Hz), 7.0 (1H， d, J ί - 3一ィル] Ν - [ [  Ηζ), 4.5 CIH,-:, J 6.0 Hz), 7.0 (1H, d, J ί-3 fil) Ν-[[
10.1 Hz), 7.6 (IH. い 7. S Hz) 7.9 (1H， ( 2 R, 3 S ) 一 3 -メ  10.1 Hz), 7.6 (IH. Yes 7. S Hz) 7.9 (1H, (2 R, 3 S) 1 3 -Me
tl, J 9.6 Hz), 8.1 till, , J = 8.0, トキシピ Πリジン一 2—  tl, J 9.6 Hz), 8.1 till,, J = 8.0, Toxipi lysine 1—
Hz), 2 (1H， del, J ， 11.5, 1.8 Hz), ィル] メチル] — Ν メ  Hz), 2 (1H, del, J, 11.5, 1.8 Hz), Yil] methyl] — Ν me
s), (1H， br s), 9.9 CIH, br s) .  s), (1H, br s), 9.9 CIH, br s).
チルペンズァミ ド  Chilpenamide
N - [ [ ( 2 R, 3 S) 1H- NMR (D SO -D6) δ 2,0-2.1 (2Hf ) 2.1 一 3 —メトキシピロリジ (3H, s), 2.8 (2 , し J - 7.1 Hz), 3.1 S.2 ンー 2—ィル] メチル] (IH, m), 3.3 (SM, ) 3, 3-3. -1 (1H> m) 3, 5- - 4 - ( 6 - [ [ 2 - ( 3.7 (4H, m), 3.9- 4.0 (1H， m)， 7. (III (1， J メチルチオ） ェチル〗 ァ 9. fi Ilz), 8. t (211, (1， J - 9. G Hz), 8.1 (2K, ミノ] イミダゾ [ 1 , 2 J ， 8.3 Hz), 8.3 (211 d， J - 8.7 Hz), ¾. a - b ] ピリ ダジン一 3 — CIH, s), 9.2 CIH, I, J ^ S.O Hz), 9.4 (i , ィル） ベンズアミ ド ^), 9.7 (IH, br s )· N-[[(2 R, 3 S) 1H- NMR (D SO -D6) δ 2,0-2.1 (2H f ) 2.1 One 3 -Methoxypyrrolidi (3H, s), 2.8 (2, J 7.1 Hz), 3.1 S.2 N-yl] methyl] (IH, m), 3.3 (SM,) 3, 3-3. -1 (1H> m) 3, 5--4-(6- [[2-(3.7 (4H, m), 3.9- 4.0 (1H, m), 7. (III (1, J methylthio) ethylase 9. fi Ilz), 8. t (211, (1, J -9. G Hz), 8.1 (2K, Mino) imidazo [1, 2 J, 8.3 Hz), 8.3 (211 d, J-8.7 Hz), ¾. A-b] pyridazine 1 3 — CIH, s) , 9.2 CIH, I, J ^ SO Hz), 9.4 (i, yl) benzamide ^), 9.7 (IH, br s) ·
1H-NMR (DMS0-D6) δ ： 〖· 2 (3Η し J = fi.9 1H-NMR (DMS0-D6) δ: 〖· 2 (3Η J = fi.9
4— ( 6— [ [ 2 - （ェ Hz), 2.0-2.1 (IH, ra), 2.1-2.2 (ίΗ， m), 2.6 チルチオ） ェチル] アミ (2H， q, J = Ί Hz), 2.8 (2H, t, い 7.【 Hz)， ノ」 イミダゾ [ 1， 2 - 3.2-3. (IH, m), 3.3 (3H, s)， 3.3-3.4 (III, b] ピリダジン— 3—ィ m), 3.5 (2H, t, J - 6.4 H?J , 3.6-3.7 (3H, m)t ル） 一 N— [ [ C 2 R, 4.0-4.0 (IH, m)， ΊΛ ClH, d, J - 9.6 Wi) , 8.0 3 S) — 3—メ トキシピ (IH, (1, J = 10.1 Ilz), 8.1 (2H , d, J = S.3 口リジン一 2 —ィル] メ Hz), 8.3 (2H， ii, J - 7.8 Ha) ; 8.3 (Ul， s)， チル] ベンズァミ ド 9.0 (IH, I, J = o.5 llz), 9.4 (1H， br s), 9.6 4— (6— [[2-(ェ Hz), 2.0-2.1 (IH, ra), 2.1-2.2 (ίΗ, m), 2.6 tilthio) ethyl] Ami (2H, q, J = Ί Hz), 2.8 (2H, t, y 7. [Hz), no] Imidazo [1, 2-3.2-3. (IH, m), 3.3 (3H, s), 3.3-3.4 (III, b] Pyridazine-3 m), 3.5 (2H, t, J-6.4 H? J, 3.6-3.7 (3H, m) t ) i N— [[C 2 R, 4.0-4.0 (IH, m), ΊΛ ClH, d, J-9.6 Wi), 8.0 3 S) — 3—Metoxipi (IH, (1, J = 10.1 Ilz), 8.1 (2H, d, J = S.3 Mouth lysine 1 −2 メ Hz), 8.3 (2H, ii, J-7.8 Ha) ; 8.3 (Ul, s), chill] benzamide 9.0 (IH, I, J = o.5 llz), 9.4 (1H, br s), 9.6
CiH, br s) .  CiH, br s).
IH-X R (DMS0-DB) δ ： \ .9-2.0 C2H, m), 2.0 (3Η, I， J = 4.1 Hz), 2.1 (IH, it, J = ! 1.5, IH-X R (DMS0-DB) δ: \ .9-2.0 C2H, m), 2.0 (3Η, I, J = 4.1 Hz), 2.1 (IH, it, J =! 1.5,
N - [ [ ( 2 R, 3 S) 3.7 Hz), 2.6 {2\, t， J - 7.3 Hz), 3.2 (1H， t 一 3 —メ トキシピロリジ J = 10.5 Hz), 3.3 H， d, J = 2.3 Hz) , 3.4 ン 2 —ィル] メチル] (3H， tt， J 15.8, 5.6 Hz), ¾ 5 (IH, dq, J = - 4 - C 6 - [ [ 3 - ( 15.0, 3.4 Hz), 3.7 (3H， til, J 12.7, 5 メチルチオ） プロピル] Hz), 4, 0-4.0 ClK, m), Ϊ, 1 CUi d(i, J = 9.9, ァミノ ] イ ミダゾ [ 1 , 2.5 Hz), 8.0 CIH, dd, J = 9.6， .7 Kz), 8. [ 2 - b] ピリダジン一 3 (2H, dd, J = 6.9, 1.8 Hz), 8 H, tiri, J 二 一ィル） ベンズァミ ド 6,6, 2, 1 Hz), S. (】H, d, J ： 3.7 Hz), 9, 0 N-[[(2 R, 3 S) 3.7 Hz), 2.6 (2 \, t, J-7.3 Hz), 3.2 (1H, t 1-3-methoxypyrrolidi J = 10.5 Hz), 3.3 H, d, J = 2.3 Hz), 3.4 2 -yl] methyl] (3H, tt, J 15.8, 5.6 Hz), ¾ 5 (IH, dq, J =-4-C 6-[[3-(15.0, 3.4 Hz ), 3.7 (3H, til, J 12.7, 5 methylthio) propyl] Hz), 4, 0-4.0 ClK, m), Ϊ, 1 CUid (i, J = 9.9, amino] imidazo [1, 2.5 Hz ), 8.0 CIH, dd, J = 9.6, .7 Kz), 8. [2-b] Pyridazine 3 (2H, dd, J = 6.9, 1.8 Hz), 8 H, tiri, J double) Benzamide 6,6, 2, 1 Hz), S. (] H, d, J: 3.7 Hz), 9, 0
(IH, i, J - 5.7 Hz), 9.4 (IH, s)， (IH, (IH, i, J-5.7 Hz), 9.4 (IH, s), (IH,
1H-NMR (D S0-D6) δ ： 1.2-し 4 {IK, m) , し 5—1H-NMR (DS0-D6) δ: 1.2- 4 (IK, m), 5
2—フルォロ - 4 - [ 6 1.7 (IH m), 1.9-2.1 (3H， m)， 2.9 3.2 (3Ht 一 [ ( 3—フルォロプロ m)， 3.0 (3H, (I, J - 40.7 Hz), 3.4-3.5 (3H， ピル） ァミノ ] イミダゾ m)r -3.6 (IH, m), 4.5—4.6 (IH, m) , 4.6-4.72—Fluoro-4-[6 1.7 (IH m), 1.9-2.1 (3H, m), 2.9 3.2 (3H t [[(3—Fluoropro m), 3.0 (3H, (I, J-40.7 Hz), 3.4-3.5 (3H, pill) amino] imidazo m) r -3.6 (IH, m), 4.5—4.6 (IH, m), 4.6-4.7
[ 1， - b] ピリダジ (IH, m)， 5.2 (IH, ddt, J = 90.5， S3.8, 2.9 I ン— 3一ィル] [ Ha), 6.7 (1H， dd, J = 9.7, 3.4 Hz), 7.3 (IH,[1, -b] Pyridazi (IH, m), 5.2 (IH, ddt, J = 90.5, S3.8, 2.9 I in 3 yl) [Ha), 6.7 (1H, dd, J = 9.7, 3.4 Hz), 7.3 (IH,
[ ( S, 4 R) 一 4— し 3 4.9 Hz), 7.5 (IH, dt， 3 - 14.7, 6.2 フル才ロピロリ ジン 2 Hz), 7, S (IH, dd， J - 9.7, 2.9 Hz), 8.1 CIH, —ィル] メチル] 一 N— (】， J = 6.3 Hz), 8.1 (IH, ddd, J = 12.6， 8.6， メチルペンズァミ ド 1,7 Hz)， 8,2 C)Hf ddd, J - 20.3, 12.0， 1.4 [(S, 4 R) 1-4-3 4.9 Hz), 7.5 (IH, dt, 3-14.7, 6.2 Full-aged ropyrrolidine 2 Hz), 7, S (IH, dd, J-9.7, 2.9 Hz) , 8.1 CIH, —yl] methyl] I N— (), J = 6.3 Hz), 8.1 (IH, ddd, J = 12.6, 8.6, methyl penamide 1,7 Hz), 8,2 C) H f ddd , J-20.3, 12.0, 1.4
Hz). 1H -瞧 (DMS0-D6) «5 ： 2.0-2.2 (411, π:), 3.2-Hz). 1H-瞧 (DMS0-D6) «5: 2.0-2.2 (411, π :), 3.2-
2—フル才ロ— 4 _ [ 6 2—Full age B — 4 _ [6
3.2 (1Η， ηι), 3.3 (3Η, s) , 3.3-3.4 (HE, ill) ,  3.2 (1Η, ηι), 3.3 (3Η, s), 3.3-3.4 (HE, ill),
― [ ( 3—フルォロプロ  ― [(3—Fluoropro
3.4 (2Η, dd, = U 2, G.6 H¾), 3+6-3.6 (2i[, ピル） ァミノ] イミダゾ 3.4 (2Η, dd, = U 2, G.6 H¾), 3 + 6-3.6 (2i [, pill) amino] imidazo
m)， S.7-3.7 (1Η, H!) 3.9 4.0 (IH, n ， 4.6  m), S.7-3.7 (1Η, H!) 3.9 4.0 (IH, n, 4.6
[ 1， 2 - ] ピリダジ  [1, 2-] Pyridazi
(IH, C, J - 5.7 Hz) 4.6 (IH， i， J - 6.0 H ）， ン— 3—ィル] N— [  (IH, C, J-5.7 Hz) 4.6 (IH, i, J-6.0 H), N—3—yl] N— [
7.2 (ίΗ, ri> J - 9.7 Hs)( 7.9 (IH, 【， J - 8.0 7.2 (ίΗ, ri> J-9.7 Hs) ( 7.9 (IH, 【, J-8.0
[ ( 2 R, 3 S) 3 - [(2 R, 3 S) 3-
Hz) 8.0 (IK, (]， J 9.7 Hz), 8.1 C1H, dd, J メ トキシピロリジン一 i Hz) 8.0 (IK, (], J 9.7 Hz), 8.1 C1H, dd, J methoxypyrrolidine i
= 8 0, 1 7 Hz), 8.2 (1H， d(]f J 12.6, 1.7 = 8 0, 1 7 Hz), 8.2 (1H, d (] f J 12.6, 1.7
ィル] メチル] ペンズ  [Mil] Penz
ILz) 8.6 (IH, 8- 8-8.8 (1J[ , m), 9. :1-9.4  ILz) 8.6 (IH, 8- 8-8.8 (1J [, m), 9.:1-9.4
アミ ド  Amido
(1H. m)， 9.7-9. fi (1H， m).  (1H. M), 9.7-9. Fi (1H, m).
1 -隱 （薦 0- D6) c5 L 8-2.2 (fill si), 2.9  1-隱 (Recommended 0- D6) c5 L 8-2.2 (fill si), 2.9
2 フルオロー 4 _ [ 6 (3H , d, J - 5.5 Hz), 3.0-^.1 (IH, m)， 3.4  2 Fluoro 4 _ [6 (3H, d, J-5.5 Hz), 3.0-^. 1 (IH, m), 3.4
- [ ( 3—フルォロプロ (^K， tlci, J 11.5, 9 Hz), 3.5— 3 6 (211， m)  -[(3—Fluoropro (^ K, tlci, J 11.5, 9 Hz), 3.5— 3 6 (211, m)
ピル） ァミノ ] イミダゾ 3.7 (IH, dt, J 14.2, 5 5 Hz), 3 8 〈1H， dt  Pill) Amino] Imidazo 3.7 (IH, dt, J 14.2, 5 5 Hz), 3 8 <1H, dt
[ 1 , 2 - b ] ピリダジ j = 14.2, 5.8 Hz) t 4- 5 (IK, t, J ).7 Hz), [1, 2-b] Pyridazi j = 14.2, 5.8 Hz) t 4-5 (IK, t, J) .7 Hz),
68  68
3 —ィル] N— [ 4.7 (IH, t， J = 5.7 Hi), 1.2 flH, 10, 1  3 — N] N— [4.7 (IH, t, J = 5.7 Hi), 1.2 flH, 10, 1
[ ( 2 S) — 1 —メ千ル H'i) , 7.9 (IH, t， J = 8.7 Hz) , 8. I (1H; il J = ピロリジン— 2 —ィル] 10. ί Hi), 8.1 (1H， rid, 】 - 10.1， 2.3 Hz) S.2 メチル] ベンズアミ ド (IH , dd, J - 12.6, 1.6 Hz), 8.6 (IH, s)， 8.8- 8.9 (III, m), 10.7 (1H， br s). [(2 S) — 1 — Thousands of H'i), 7.9 (IH, t, J = 8.7 Hz), 8. I (1H ; il J = Pyrrolidine — 2 — Yil) 10. ί Hi), 8.1 (1H, rid,]-10.1, 2.3 Hz) S.2 Methyl] benzamide (IH, dd, J-12.6, 1.6 Hz), 8.6 (IH, s), 8.8-8.9 (III, m), 10.7 (1H, br s).
1H-隱 (DMS0-D6) 6 ： 1.7-2.1 (71し m)， 2.1  1H- 隱 (DMS0-D6) 6: 1.7-2.1 (71 m), 2.1
一フルォ Π - 4 - [ 6 2.2 (IH, tn). 2,9 C3H, d， J - 4.6 Kz), 3. ϋ- :ΐ.  Fluoro Π-4-[6 2.2 (IH, tn). 2,9 C3H, d, J-4.6 Kz), 3. ϋ-: ΐ.
— [ (4 フルォ Πプチ (IH, m). -¾.4 (211, ηι)， 3.5-3.6 (2Η, m>，  — [(4 Fluo Π Petit (IH, m). -¾.4 (211, ηι), 3.5-3.6 (2Η, m>,
ル） ァミノ] イミダゾ [ 3,7 (Uし dt, J = 14.1, ϋ.： j z)f 8 (IK, rit, Le) Amino] Imidazo [3,7 (U and dt, J = 14.1, ϋ .: jz) f 8 (IK, rit,
1， 2™ b] ピリダジン J = 14, 2, ) Hz), 4.5 (1H， t， J = 5, 5 Hz),  1, 2 ™ b] pyridazine J = 14, 2,) Hz), 4.5 (1H, t, J = 5, 5 Hz),
69  69
- 3 —ィル] — N - [ [ 4.6 (IH, t. J - 5.7 Hz) , 7, 2 (1H， d， J - 10.  -3 —il] — N-[[4.6 (IH, t. J-5.7 Hz), 7, 2 (1H, d, J-10.
( 2 S) - I —メチルビ Hz), 7.9 (IK 1, J 8.0 H^), 8.0 (li[， d, J  (2 S)-I —Methylbi Hz), 7.9 (IK 1, J 8.0 H ^), 8.0 (li [, d, J
口リジン 2 —ィル] メ 9.6 Hz), S.1 (111 dd, J = 1.8 Hz), 8.2  Mouth lysine 2 — me] 9.6 Hz), S.1 (111 dd, J = 1.8 Hz), 8.2
チル〗 ベンズァミ ド (IH, dd, J = 12. Ei, 1.6 Hz), 8.6 (1H， s)， 8.8  Chill benzamide (IH, dd, J = 12. Ei, 1.6 Hz), 8.6 (1H, s), 8.8
8.9 UH， m), 10, fi (IH, br s) .  8.9 UH, m), 10, fi (IH, br s).
VMR (DMS0-D6) δ 2.0-2, 1 (3H， m). U- VMR (DMS0-D6) δ 2.0-2, 1 (3H, m). U-
2 —フルォ Π N— [ [ 2 —Fluo Π N— [[
2.5 (IIし in), 3.0 (3H， s), 3, 4-3, (3H, m)，  2.5 (II and in), 3.0 (3H, s), 3, 4-3, (3H, m),
( S , R ) 4 フ  (S, R) 4
3.8 9 (3H， m), 4.0 (IH, dd, J - 30. , 14.0 ルォ口— 1 ーメチルビ ]  3.8 9 (3H, m), 4.0 (IH, dd, J-30., 14.0 Luo mouth-1-methylbi]
Kz)， 4. Γ, (IH, t， J 二 5.7 Hz), 4 7 (lit, t， J  Kz), 4. Γ, (IH, t, J 2 5.7 Hz), 4 7 (lit, t, J
リジン— 2 —ィル〗 メチ  Lysine— 2 —
ί>.7 Hz) , 5.4 (11し rit, j & 3.6， '1.1 H ) , 7.2 ル] _ 4一 L 6 - [ ( 3  ί> .7 Hz), 5.4 (11 rit, j & 3.6, '1.1 H), 7.2 Le] _ 4 1 L 6-[(3
(IH d; J - 10.1 Hz), 7.9 (IH, ί, J = H.0 (IH d ; J-10.1 Hz), 7.9 (IH, ί, J = H.0
一フルォロプ nピル） ァ  One Fluorop n pill)
Ha) 8.0 C1H, br s)， 8.0 (IH, (1， J - 10. ί  Ha) 8.0 C1H, br s), 8.0 (IH, (1, J-10. ί)
ミノ] イミダゾ [ 1 , 2  Mino] Imidazo [1, 2
Hz) 8.1 (1H， dd, J - 8.0, 1.1 Hz), 8.2 (IH, b] ピリダジン _ 3 _  Hz) 8.1 (1H, dd, J-8.0, 1.1 Hz), 8.2 (IH, b] Pyridazine _ 3 _
dd, 12. -1, 1.4 Hz) ， 8.S (IH, s), 8. S (IH, ィル] ベンズァミ ド  dd, 12. -1, 1.4 Hz), 8.S (IH, s), 8. S (IH, Yil) benzamide
br  br
1II-N R {DMS0-D6) δ ： 1.0 (3H, f1， J = 6.4  1II-N R (DMS0-D6) δ: 1.0 (3H, f1, J = 6.4
2―フルォロ _ 4 _ [ 6 Hz), 1. 6 (1H， ra)， Ϊ.7-1.8 (IH, HI) , 1.9- ― [ ( 4 フルオロー 3 2.1 (2H， m)， 2.3-2.4 (iH, m), 3.4-3.6 ( H,  2-Fluoro _ 4 _ [6 Hz), 1.6 (1H, ra), Ϊ.7-1.8 (IH, HI), 1.9- ― [(4 Fluoro 3 2.1 (2H, m), 2.3-2.4 ( iH, m), 3.4-3.6 (H,
—メチルブチル） ァミノ m)， 3, 7-3.8 (2H3 m)， 3.9-4.0 (111, m), 4.3 —Methylbutyl) amino m), 3, 7-3.8 (2H 3 m), 3.9-4.0 (111, m), 4.3
] イミダゾ [ 1 ， 2— b (IH, d, J = 5,5 Hs), 4.4 UH, d, J = 5. Hz)，  ] Imidazo [1, 2—b (IH, d, J = 5,5 Hs), 4.4 UH, d, J = 5. Hz),
] ピリダジン— 3—ィル 5.5 (IH, (it, J = 5S.2， 3.2 Hz), 7.2 (IK, d. J  ] Pyridazine—3-yl 5.5 (IH, (it, J = 5S.2, 3.2 Hz), 7.2 (IK, d. J
] - N - [ [ ( 2 S , 4 - 9.G Hz), 7.9 (LH， t , J = 8.0 Hz), Β.ϋ (IK,  ]-N-[[(2 S, 4-9. G Hz), 7.9 (LH, t, J = 8.0 Hz), Β.ϋ (IK,
R) — 4 フルォロピロ d, J - 10. I Hs), 8.1 C1H, dd, J = S.3， 1-8  R) — 4 Fluoropiro d, J-10. I Hs), 8.1 C1H, dd, J = S.3, 1-8
リジン一 2—ィル] メチ Kz), 8.3 (IH, dd, J = 12.4t 1.4 Hz), 8.6 (IH, ル] ペンズァミ ド s)， 8.7-8.8 (IH, m), 9.5 (IH, br s)， 10.0 Lysine 2-yl] methyl Kz), 8.3 (IH, dd, J = 12.4 t 1.4 Hz), 8.6 (IH, Le] pendamide s), 8.7-8.8 (IH, m), 9.5 (IH, br s), 10.0
(IH, br s).  (IH, br s).
[0394] [試験例 1] 被験物質の in vitro試験（1):LPS誘導一マウス末梢全血細胞からの TNF—《遊離の抑制作用試験 [0394] [Test Example 1] In vitro test of test substance (1): LPS-induced TNF from a mouse peripheral whole blood cell — << Release inhibitory action test
[0395] 6週齢の BALB/cマウスをエーテル麻酔し、抗凝固剤としてへパリンを用い、下大 静脈より採血した。血液 10 Lにチュルク染色液（ナカライテスク株式会社）（90 ^L) を加えて赤血球を溶解し、白血球数を測定した。マウス全血を RPMI— 1640培地で 希釈して、白血球数を 250， 000個/ mLに調整した。 [0395] Six-week-old BALB / c mice were anesthetized with ether, and blood was collected from the inferior vena cava using heparin as an anticoagulant. To 10 L of blood, Turku stain (Nacalai Tesque) (90 ^ L) was added to lyse red blood cells, and the white blood cell count was measured. Whole mouse blood in RPMI-1640 medium After dilution, the white blood cell count was adjusted to 250,000 / mL.
被検物質の DMSO溶液を 96— well plateに 20 L/well (DMSO終濃度 0· 3% )分注し、上記の調製したマウス全血を 160 L/well添加した。さらに、 LPS溶液を 20 H
Figure imgf000152_0001
β g/mL ; E. Coli.〇111 : B4、 Calbiochem)添カロし、 37 °Cで 4時間加温した。 96— well plateを遠心分離（2000rpm、 5分間）し、上清の 1 50 a Lを回収し、 ELISA [マウス TNF (Mono/Mono) ELISA set, BDバイオサ ィエンス]により、 TNF— a量を定量した。 A DMSO solution of the test substance was dispensed into a 96-well plate at 20 L / well (DMSO final concentration: 0.3%), and 160 L / well of the prepared mouse whole blood was added. Add LPS solution to 20 H
Figure imgf000152_0001
β g / mL; E. Coli. ○ 111: B4, Calbiochem) was added and heated at 37 ° C for 4 hours. Centrifuge the 96-well plate (2000 rpm, 5 minutes), collect 150 a L of the supernatant, and quantify the amount of TNF-a by ELISA [Mouse TNF (Mono / Mono) ELISA set, BD Bioscience] did.
[0396] 溶媒 (DMSO)対照群と被検物質添加群の TNF— a量の比から被検物質の阻害 活性（％)を求め、被検物質の 50%抑制濃度 [IC M) ]を算出した。被験物質の [0396] The inhibitory activity (%) of the test substance was determined from the ratio of TNF-a in the solvent (DMSO) control group and the test substance addition group, and the 50% inhibitory concentration [IC M)] of the test substance was calculated. did. Of the test substance
50  50
評価結果 [IC 値 M ) ]を、下記の表に示す。  The evaluation results [IC value M)] are shown in the following table.
50  50
[0397] [表 3]  [0397] [Table 3]
Figure imgf000152_0002
Figure imgf000152_0002
[0398] 本試験の結果、本発明化合物はマウス末梢全血細胞を用いた LPS誘導による TN F— αの遊離抑制作用を示した。実施例 4、 7、 8、 13、 16、 20及び 22の化合物は、 0. 65〜0. 91〃 Μの IC 値を示した。 [0398] As a result of this test, the compound of the present invention showed an inhibitory effect on the release of TNF-α by LPS induction using mouse peripheral whole blood cells. The compounds of Examples 4, 7, 8, 13, 16, 20, and 22 exhibited IC values from 0.65 to 0.91〃.
[試験例 2] 被験物質の in vitro試験（2)： LPS誘導ーヒト末梢全血細胞からの TN F—《遊離の抑制作用試験 [Test Example 2] In vitro test of test substance (2): LPS induction-TNF from human peripheral whole blood cells-<< Inhibition of release action
[0399] 社内ポランティアから抗凝固剤にへパリンを用いて、上腕静脈より採血した。血液 1 0 しにチュルク染色液（ナカライテスタ株式会社）（90 を加えて、赤血球を溶解 し、白血球数を測定した。ヒト全血を RPMI— 1640培地で希釈して、白血球数を 25 0, 000個/ mLに調整した。 [0399] Blood was collected from the brachial vein from an in-house volunteer using heparin as an anticoagulant. Blood 10 and Turku staining solution (Nacalai Testa Co., Ltd.) (90 were added to lyse red blood cells and the white blood cell count was measured. Human whole blood was diluted with RPMI-1640 medium to obtain a white blood cell count of 25. Adjusted to 0,000 cells / mL.
[0400] 被検物質の DMSO溶液を 96— well plateに 20 / L/well (DMSO終濃度 0. 3 %)分注し、上記の調製したヒト全血を 160 L/well添加した。さらに、 LPS溶液を
Figure imgf000153_0001
μ g/mL ; E. Coli. Ol 11 : B4、 Calbiochem)添カロし、 37 °Cで 4時間加温した。 96— well plateを遠心分離して（2000rpm、 5分間）、上清の 150 μ Lを回収し、 ELISA (OptEIA, BDバイオサイエンス）により、 TNF— a量を 定量した。 [0400] The DMSO solution of the test substance was dispensed into a 96-well plate at 20 / L / well (DMSO final concentration 0.3%), and the prepared human whole blood was added at 160 L / well. In addition, the LPS solution
Figure imgf000153_0001
μg / mL; E. Coli. Ol 11: B4, Calbiochem) was added and heated at 37 ° C for 4 hours. The 96-well plate was centrifuged (2000 rpm, 5 minutes), 150 μL of the supernatant was collected, and the amount of TNF-a was quantified by ELISA (OptEIA, BD Bioscience).
[0401] 溶媒 (DMSO)対照群と被検物質添加群の TNF— a量の比から被検物質の阻害 活性（％)を求め、被検物質の 50%抑制濃度 [IC M) ]を算出した。被験物質の  [0401] The inhibitory activity (%) of the test substance was determined from the ratio of TNF-a in the solvent (DMSO) control group and the test substance addition group, and the 50% inhibitory concentration [IC M)] of the test substance was calculated. did. Of the test substance
50  50
評価結果 [IC 値 M ) ]を、下記の表に示す。  The evaluation results [IC value M)] are shown in the following table.
50  50
[0402] [表 4]  [0402] [Table 4]
Figure imgf000153_0002
Figure imgf000153_0002
[0403] 本試験の結果、本発明化合物はヒト末梢全血細胞を用いた LPS誘導による TNF— αの遊離抑制作用を示した。実施例 4、 7、 16、 20及び 22の化合物は、 0. 23-0. 65〃^の1じ ィ直を示した。  [0403] As a result of this test, the compound of the present invention showed an inhibitory effect on the release of TNF-α by LPS induction using human peripheral whole blood cells. The compounds of Examples 4, 7, 16, 20, and 22 showed a straight line of 0.23-0.65%.
50  50
[試験例 3] 被験物質の in vitro試験（3)： LPS誘導ーヒト THP— 1細胞からの TN F— «遊離の抑制作用試験 [Test Example 3] In vitro test of test substance (3): LPS induction-TNF from human THP-1 cells
[0404] 100nMカルシトリオール (VD3 :和光純薬工業株式会社)存在下で 4〜5日間培養 したヒト単球系白血病細胞株 THP— 1 (7. 5 X 105 cells/mU、被験物質の DMS O溶液及び LPS d g/mL E. Coli. 0111 : B4、 Calbiochem)を同時添加し、 インキュベート開始 4時間後の培養上清中 TNF— α濃度を測定した。 TNF—《濃 度は市販の ELISAキット（〇ptEIA、 BDバイオサイエンス）で測定した。 [0405] 溶媒 (DMSO)対照群と被検物質添加群の TNF— a量の比から被検物質の阻害 活性 (％)を求め、被検物質の 50%抑制濃度 [IC M) ]を算出した。被験物質の [0404] Human monocytic leukemia cell line THP—1 (7.5 × 10 5 cells / mU, DMS of test substance) cultured in the presence of 100 nM calcitriol (VD3: Wako Pure Chemical Industries, Ltd.) for 4-5 days O solution and LPS dg / mL E. Coli. 0111: B4, Calbiochem) were added simultaneously, and the TNF-α concentration in the culture supernatant was measured 4 hours after the start of incubation. TNF-<< concentration was measured with a commercially available ELISA kit (0 ptEIA, BD Bioscience). [0405] The inhibitory activity (%) of the test substance was calculated from the ratio of TNF-a in the solvent (DMSO) control group and the test substance addition group, and the 50% inhibitory concentration [IC M)] of the test substance was calculated. did. Of the test substance
50  50
評価結果 [IC 値 M ) ]を、下記の表に示す。  The evaluation results [IC value M)] are shown in the following table.
50  50
[0406] [表 5]  [0406] [Table 5]
Figure imgf000154_0001
Figure imgf000154_0001
[0407] 本試験の結果、本発明化合物はマウス末梢全血細胞を用いた LPS誘導による TNF αの遊離抑制作用を示した。実施例 4、 7、 8、 13、 16、 20、 21及び 22の化合物 (ま、 0. 29〜0. 84 μ Μ<Ό10 ィ直を示した。 [0407] As a result of this test, the compound of the present invention showed an inhibitory effect on the release of TNFα by LPS induction using mouse peripheral whole blood cells. The compounds of Examples 4, 7, 8, 13, 16, 20, 21 and 22 (between 0.29 and 0.84 μΜ <Ό10 were shown).
50  50
[試験例 4] 被験物質のマウス in vivo試験（1 ) : LPS誘導による TNF— α産生の 抑制作用試験 [Test Example 4] In vivo test of test substance in mice (1): LPS-induced TNF-α production inhibitory action test
[0408] 6週齢の雄性 Balb/cマウスを、コントロール群と被検物質投与群に分けた。被検 物質を 0. 5%メチルセルロース溶液 (w/v%)で懸濁し、 10mL/kgを経口投与し た。コントロール群は、 0. 5%メチルセルロース溶液 (w/v%)を、同様に経口投与し た。被検物質投与後 30分後に、生理食塩水 ImLあたり 0. 02mgの LPSを含む溶液 を尾静脈から静脈内投与した。 LPS投与の 1時間後に、エーテル麻酔下、下大静脈 より抗凝固剤にへパリンを用いて採血した。採取した血液を、遠心分離（2000rpm, 4°C、 30分間）して、血漿を回収した。血漿の一部を PBSで 10倍に希釈して、 ELIS Aキット（マウス TNF (Mono/Mono) ELISA set, BDバイオサイエンス）で、 TNF a量を測定した。  [0408] Six-week-old male Balb / c mice were divided into a control group and a test substance-administered group. The test substance was suspended in 0.5% methylcellulose solution (w / v%), and 10 mL / kg was orally administered. In the control group, 0.5% methylcellulose solution (w / v%) was orally administered in the same manner. Thirty minutes after administration of the test substance, a solution containing 0.02 mg of LPS per mL of physiological saline was administered intravenously from the tail vein. One hour after LPS administration, blood was collected from the inferior vena cava using heparin as an anticoagulant under ether anesthesia. The collected blood was centrifuged (2000 rpm, 4 ° C, 30 minutes), and plasma was collected. A part of the plasma was diluted 10-fold with PBS, and the amount of TNFa was measured with an ELIS A kit (mouse TNF (Mono / Mono) ELISA set, BD Bioscience).
[0409] 阻害活性（％)は、溶媒 (0. 5 %メチルセルロース溶液)対照群と被検物質添加群 の TNF— a量の比から求めた。 [0409] Inhibitory activity (%) was determined by solvent (0.5% methylcellulose solution) control group and test substance addition group. It was calculated from the ratio of the amount of TNF-a.
[0410] [表 6] [0410] [Table 6]
Figure imgf000155_0001
Figure imgf000155_0001
[0411] 本試験の結果、本発明化合物はマウスモデルにおいて、 LPS誘導による TNF— a 産生の抑制作用を示した。実施例 20及び 22の化合物は、 30mg/kgの経口投与で 、それぞれ 72及び 65%の優れた阻害効果を示した。 [0411] As a result of this test, the compound of the present invention showed an inhibitory effect on LPS-induced TNF-a production in a mouse model. The compounds of Examples 20 and 22 showed excellent inhibitory effects of 72 and 65%, respectively, at an oral dose of 30 mg / kg.
[試験例 5] 被験物質の in vivo試験（2) :マウスコラーゲン誘発関節炎モデルによ る試験 [Test Example 5] In vivo test of test substance (2): Test using mouse collagen-induced arthritis model
[0412] 7週齢の DBA/lj雌マウス（日本エスエルシー株式会社）に 3%— Typellコラーゲ ン（コラーゲン技術研修会）と FCA (Difco)の等量ェマルジヨンをマウス尾根部皮内 投与（0. lmL)して感作した。初回感作から 21日目に同量のコラーゲン及び FCAェ マルジヨンを腹部に皮内投与して追感作し、関節炎を惹起した。  [0412] Seven-week-old DBA / lj female mice (Japan SLC Co., Ltd.) were administered 3% —typell collagen (collagen technical workshop) and FCA (Difco) in the same amount of emulsion (0) 1 mL) and sensitized. On the 21st day after the first sensitization, the same amount of collagen and FCA emulsion was administered intradermally to the abdomen to sensitize and induce arthritis.
関節炎の程度は、四肢の腫脹を 5段階にスコア化して判定した。また、体重変化に対 する作用も同時に検討した。  The degree of arthritis was determined by scoring limb swelling into 5 levels. The effect on body weight change was also examined.
被験物質は 0. 5%メチルセルロース溶液 (w/v%)に溶解又は懸濁し、追感作日か ら 14日間、 1日 1回を経口投与した。  The test substance was dissolved or suspended in 0.5% methylcellulose solution (w / v%) and orally administered once a day for 14 days from the day of sensitization.
[0413] 関節炎の程度は、四肢の腫脹を 5段階でスコア化して試験した (表)。関節炎スコア は、各スコアリング日の関節炎を個体ごとに合計して求めた。対照群 (被験物質非投 与群)及び被検物質投与群の関節炎スコアの平均値を求め表示した。対照群及び 被検物質投与群の関節炎スコアの平均スコアを比較することによって被験物質の効 果を評価した。  [0413] The degree of arthritis was examined by scoring limb swelling in 5 stages (Table). The arthritis score was calculated by adding the arthritis on each scoring day for each individual. The average value of the arthritis score of the control group (the test substance non-administration group) and the test substance administration group was obtained and displayed. The effect of the test substance was evaluated by comparing the mean arthritis scores of the control group and the test substance-administered group.
[0414] [表 7] スコア 関節炎 [0414] [Table 7] Score arthritis
0 変化なし  0 No change
0 . 5 指に弱い腫脹あり  0.5 weak swelling on fingers
1 指骨 ·足根骨周囲に弱い腫脹あり  1 There is weak swelling around the phalanges and tarsal bones
2 全体に中程度の腫脹あり  2 Overall moderate swelling
3 足全体に強い腫脹あり  3 Strong swelling on the entire foot
[0415] 本試験の結果、本発明化合物はマウスコラーゲン誘発関節炎モデルにおいて、抑 制作用を示した。投与開始 14日目のスコア力 S、病態コントロール群である対照群で 8 . 29であるのに対し、実施例 20の化合物を 30mg/kgの経口投与した群では、 3. 2 9であり、優れた関節炎の阻害効果を示した。 [0415] As a result of this test, the compound of the present invention was shown to be used for suppression in a mouse collagen-induced arthritis model. On the 14th day from the start of administration, the score power S was 8.29 in the control group which was the pathological condition control group, whereas it was 3.29 in the group to which the compound of Example 20 was orally administered at 30 mg / kg, Excellent arthritis inhibitory effect.
[試験例 6] 被験物質の in vivo試験（3)：ラットアジュバント関節炎モデルによる試 験 [Test Example 6] In vivo test of test substance (3): Test using rat adjuvant arthritis model
[0416] 7週齢の LEW/Crlj雌ラット（Wistar Lewis)の左足足踱皮内に 6mg/mLの M . butyricumを含むアジュバント（0. lmUを投与して関節炎を惹起した。 M. butyr icumを含むアジュバントは、 M. butyricum加熱死菌（lOOmg)をメノーの乳鉢で十 分粉砕し、流動パラフィン（16· 6ml)を加えて混和し、テフロン (登録商標)製ホモジ ナイザーに取り移して懸濁した後、 5ml用アンプルに 2〜3mlずつ分注し、オートタレ ーブで滅菌（121°C, 20分間）して使用した。  [0416] 7-week-old LEW / Crlj female rats (Wistar Lewis) induced arthritis by administering an adjuvant (0.lmU) containing 6 mg / mL M. butyricum in the left footpad crust. Adjuvant containing M. butyricum heat-killed bacteria (lOOmg) is thoroughly pulverized in a Menor mortar, mixed with liquid paraffin (16.6 ml), transferred to a Teflon (registered trademark) homogenizer and suspended. After turbidity, 2 to 3 ml each was dispensed into a 5 ml ampoule, and sterilized (121 ° C, 20 minutes) with an auto-turve.
[0417] 被験物質は 0. 5%メチルセルロース溶液 (w/v%)に溶解又は懸濁し、感作（day 0) 4時間前に初回投与し、 21日間、 1日 1回を経口投与した。  [0417] The test substance was dissolved or suspended in 0.5% methylcellulose solution (w / v%), initially administered 4 hours before sensitization (day 0), and orally administered once a day for 21 days.
[0418] ラット左右後肢の腫脹を足容積測定装置 (MK500)で測定し、左右前肢、耳、後肢 及び尾の関節炎の程度を 0〜5の 11段階に分けてスコア化した (表）。また、屠殺時 に左右後肢の X線撮影（ソフテックス）し、骨の変化を 0〜5の 11段階にスコア化した（ 表）。関節炎スコアは、各スコアリング日の関節炎を個体ごとに合計して求めた。対照 群 (被験物質非投与群)及び被検物質投与群の関節炎スコアの平均値を求め表示 した。対照群及び被検物質投与群の関節炎スコアの平均スコアを比較することによつ て被験物質の効果を評価した。  [0418] Rat left and right hind limb swelling was measured with a paw volume measuring device (MK500), and the degree of arthritis of the left and right forelimbs, ears, hind limbs and tail was divided into 11 grades from 0 to 5 (Table). At the time of sacrifice, radiographs of the left and right hind limbs (Softex) were performed, and bone changes were scored in 11 grades from 0 to 5 (Table). The arthritis score was obtained by adding the arthritis on each scoring date for each individual. The average value of arthritis scores in the control group (test substance non-administration group) and the test substance administration group was obtained and displayed. The effect of the test substance was evaluated by comparing the mean arthritis scores of the control group and the test substance-administered group.
[0419] [表 8] スコア 関節炎 骨変化 [0419] [Table 8] Score arthritis bone changes
0 変化なし 変化なし  0 No change No change
0 . 5 部分的な発赤 部分的なびらん  0.5 Partial redness Partial erosion
1 全体的な発赤又は部分的な浮腫 全体的なびらん  1 Overall redness or partial edema Overall erosion
1 . 5 弱い全体的な浮腫 全体的な弱い骨の増殖 1.5 Weak global edema Overall weak bone growth
2 部分的な中程度の浮腫 部分的な中程度の骨の増殖2 Partial moderate edema Partial moderate bone growth
2 . 5 全面積の 1 2が中程度の浮腫 全面積の 1 / 2が中程度の骨の 増殖 2.5 Total area 1 2 is moderate edema Total area 1/2 is medium bone growth
3 全体的な中程度の浮腫 全体的な中程度の骨の増殖 3 Overall moderate edema Overall moderate bone growth
3 . 5 部分的な強い浮腫 部分的な強い骨の増殖3.5 Partial strong edema Partial strong bone growth
4 全体的な強い浮腫 全体的な強い骨の増殖4 Global strong edema Global strong bone growth
4 . 5 部分的な強烈な浮腫 部分的な強烈な骨の増殖4.5 Partial intense edema Partial intense bone growth
5 全体的な強烈な浮腫 全体的な強烈な骨の増殖 5 Overall intense edema Overall intense bone growth

Claims

請求の範囲 The scope of the claims
[1] 下記の一般式 (I)  [1] The following general formula (I)
[化 1コ  [Chemical 1
Figure imgf000158_0001
Figure imgf000158_0001
[式中、 R1は、水素原子又は C1〜C6アルキル基を示し、 [Wherein R 1 represents a hydrogen atom or a C1-C6 alkyl group,
R2は、置換基を有していてもよい C1〜C6アルキル基又は C3〜C7シクロアルキル 基を示し、 R 2 represents an optionally substituted C1-C6 alkyl group or C3-C7 cycloalkyl group,
環 Aは、ベンゼン環、或いは、 5又は 6員の芳香族複素環を示し、  Ring A represents a benzene ring or a 5- or 6-membered aromatic heterocycle,
Xは、水素原子であるか、或いは、同一又は異なって、ハロゲノ基、 C1〜C6アルキ ル基、ハロゲノ C1〜C6アルキル基、 C1〜C6アルコキシ C1〜C6アルキル基、水酸 基、 C1〜C6アルコキシ基、ハロゲノ C1〜C6アルコキシ基、 C1〜C6ァノレコキシ C1 〜C6アルコキシ基、カルボキシ基、 C1〜C6アルコキシカルボニル基、シァノ基、力 ルバモイル基、 N—モノ（C1〜C6アルキル）力ルバモイル基、 N, N—ジ（C1〜C6ァ ルキル）力ルバモイル基、アミノ基、モノ（C1〜C6アルキル）アミノ基、ジ（C1〜C6ァ ルキル）アミノ基、 C1〜C6アルキルチオ基、 C1〜C6アルキルスルホニル基及びニト 口基からなる群より選ばれる 1〜3個の基を示し、  X is a hydrogen atom, or the same or different, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a hydroxyl group, a C1-C6 An alkoxy group, a halogeno C1-C6 alkoxy group, a C1-C6 anorecoxy C1-C6 alkoxy group, a carboxy group, a C1-C6 alkoxycarbonyl group, a cyano group, a force rubamoyl group, an N-mono (C1-C6 alkyl) force rubermoyl group, N, N-di (C1-C6 alkyl) force rubamoyl group, amino group, mono (C1-C6 alkyl) amino group, di (C1-C6 alkyl) amino group, C1-C6 alkylthio group, C1-C6 alkyl 1 to 3 groups selected from the group consisting of a sulfonyl group and a nitro group are shown,
Yは、下記の式（a)〜 又は（V)  Y is the following formula (a) to or (V)
[化 2] [Chemical 2]
Figure imgf000159_0001
Figure imgf000159_0001
(v)  (v)
(式中、 R3a、 R3b、 R3c、 R3d、 R3e、 R3f、 R 及び R3vは、同一又は異なって、水素原子 又は C1〜C6アルキル基を示し、 (Wherein R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R and R 3v are the same or different and represent a hydrogen atom or a C1-C6 alkyl group,
R4a、 R5a、 R4b、 R5b、 R4c、 R5c、 R4d、 R5d、 R4h、 R5h、 R4i、 R5i、 R4j及び R5jは、同一又は 異なって、水素原子、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C1〜C6 アルコキシ C1〜C6アルキル基、C3〜C7シクロアルキル基又は C3〜C7シクロアル キル C1〜C6アルキル基を示す力、、或いは、 R 4a , R 5a , R 4b , R 5b , R 4c , R 5c , R 4d , R 5d , R 4h , R 5h , R 4i , R 5i , R 4j and R 5j are the same or different and are hydrogen atoms C1-C6 alkenoquinole group, halogeno C1-C6 alkyl group, C1-C6 alkoxy C1-C6 alkyl group, C3-C7 cycloalkyl group or C3-C7 cycloalkyl C1-C6 alkyl group, or
R4aと R5a、 R4bと R5b、 R4cと R5c、 R4dと R5d、 R4hと R5h、 R4iと R5i、及び R4jと R5jは、同一又 は異なって、 2つの基が結合する窒素原子と一体化して 4〜7員の含窒素脂肪族複 素環 (この含窒素脂肪族複素環は、ハロゲノ基、 C1〜C6アルキル基、ハロゲノ Cl〜 C6ァノレキノレ基、 C1〜C6アルコキシ C1〜C6アルキル基、水酸基、 C1〜C6アルコ キシ基、ハロゲノ C1〜C6アルコキシ基及び C1〜C6アルコキシ C1〜C6アルコキシ 基からなる群より選ばれる基で 1〜3個置換されてもよい。）を形成してもよいことを示 し、 R 4a and R 5a , R 4b and R 5b , R 4c and R 5c , R 4d and R 5d , R 4h and R 5h , R 4i and R 5i , and R 4j and R 5j are the same or different, Combined with the nitrogen atom to which the two groups are bonded, a 4- to 7-membered nitrogen-containing aliphatic heterocyclic ring (this nitrogen-containing aliphatic heterocyclic ring is a halogeno group, a C1-C6 alkyl group, a halogeno Cl-C6 anolequinole group, C1-C6 alkoxy C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group, and C1-C6 alkoxy group substituted with 1-3 groups selected from C1-C6 alkoxy group ) May be formed, and
R4e、 R4f及び R4gは、同一又は異なって、水素原子、 C1〜C6アルキル基、ノヽロゲノ C ；!〜 C6ァノレキノレ基、 C1〜C6アルコキシ C1〜C6アルキル基、 C3〜C7シクロアルキ ノレ基、 C 3〜 C 7シクロアルキル C；!〜 C 6アルキル基又はフエニル C；!〜 C 6アルキノレ 基（このフエニル C1〜C6アルキル基のフエニル基は、ハロゲノ基、 C1〜C6ァノレキノレ 基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換され ていてもよい。）を示し、 R 4e , R 4f and R 4g are the same or different and each represents a hydrogen atom, a C1-C6 alkyl group, a neurogeno C;! -C6 alkanoleno group, a C1-C6 alkoxy C1-C6 alkyl group, a C3-C7 cycloalkyl. Nore group, C 3 to C 7 cycloalkyl C;! To C 6 alkyl group or phenyl C;! To C 6 alkynole group (the phenyl group of this phenyl C1 to C6 alkyl group is a halogeno group, C1 to C6 ananoleno group, 1 to 3 groups may be substituted with a group selected from the group consisting of a hydroxyl group and a C1-C6 alkoxy group).
R6a、 R6b、 R7a、 R7b、 R8a、 R8b、 R9a、 R9b、 R10b及び Rub(ま、同一又 (ま異なって、水素 原子、ハロゲノ基、 C 1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C 1〜C6ァ ルコキシ C1〜C6アルキル基、水酸基、 C1〜C6アルコキシ基、ハロゲノ C1〜C6ァ ルコキシ基又は C1〜C6アルコキシ C1〜C6アルコキシ基を示し、 R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9a , R 9b , R 10b and R ub (or the same or different, a hydrogen atom, a halogeno group, a C 1 to C 6 anolenoquinole Group, halogeno C1-C6 alkyl group, C1-C6 alkyloxy C1-C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy C1-C6 alkoxy group,
„ 12c „ 12d „ 12e „ 12f „ 12g „ 12h „ 12i „ 12j „ 12v „ 13c „ 13d „ 13e „ 13f „ 13g „ 1 „12c„ 12d „12e„ 12f „12g„ 12h „12i„ 12j „12v„ 13c „13d„ 13e „13f„ 13g „1
J 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 、K_ 3h、 R13l、 R13j、 R13v、 R14c、 R14d、 R14e、 R14f、 R14\ R14h、 R14l、 R14j及び R14vは、同一 又は異なって、水素原子、ハロゲノ基、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アル キル基、 C1〜C6アルコキシ C1〜C6アルキル基、水酸基、 C1〜C6アルコキシ基、 ハロゲノ C1〜C6アルコキシ基又は C1〜C6アルコキシ C1〜C6アルコキシ基を示し k、 1、 m、 n、 o及び pは、それぞれ、 0、 1又は 2を示し、 qは、 1又は 2を示し、 J, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_, K_ 3 h, R 13l, R 13j, R 13v, R 14c, R 14d, R 14e, R 14f , R 14 \ R 14h , R 14l , R 14j and R 14v are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 alkanoleno group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1- C6 alkyl group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy C1-C6 alkoxy group represents k, 1, m, n, o and p are 0, 1 or 2 respectively. Q represents 1 or 2,
Vは、モルホリノ基を示す。）で表されるいずれか 1つの基を示す。 ]で表される化合物 V represents a morpholino group. ) Represents one of the groups represented. Compound represented by
、その塩又はそれらの溶媒和物。 , Salts thereof or solvates thereof.
[2] 一般式 (I)中の R2が、置換基を有していてもよい C1〜C6アルキル基である請求項 1 に記載の化合物、その塩又はそれらの溶媒和物。 [2] The compound according to claim 1, a salt thereof or a solvate thereof, wherein R 2 in the general formula (I) is an optionally substituted C1-C6 alkyl group.
[3] 置換基を有していてもよい C1〜C6アルキル基力 C1〜C6ァノレキノレ基、又は、下記 の [3] C1-C6 alkyl group which may have a substituent C1-C6 alkenoquinole group, or
ハロゲノ基、  Halogeno group,
C3〜C7シクロアルキル基、  A C3-C7 cycloalkyl group,
フエニル基（このフエニル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C；!〜 C6アルコキシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、  A phenyl group (this phenyl group may be substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 anolenoquinole group, a hydroxyl group and C;! -C6 alkoxy group),
5又は 6員の芳香族複素環基 (この芳香族複素環基は、ハロゲノ基、 C1〜C6アルキ ル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換さ れていてもよい。）、 4〜7員の脂肪族複素環基 (この脂肪族複素環基は、ノ、ロゲノ基、 C1〜C6アルキル 基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換され ていてもよい。）、 5- or 6-membered aromatic heterocyclic group (this aromatic heterocyclic group is substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group. May be) 4- to 7-membered aliphatic heterocyclic group (this aliphatic heterocyclic group is substituted with 1 to 3 groups selected from the group consisting of a noro, a logeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group) May be done)
4〜7員の脂肪族複素環基— CO—基 (この脂肪族複素環基は、ハロゲノ基、 C1〜C 6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3 個置換されていてもよい。）、  4- to 7-membered aliphatic heterocyclic group—CO— group (this aliphatic heterocyclic group is a group selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group. 3 may be substituted.),
水酸基、 Hydroxyl group,
C1〜C6アルコキシ基、  A C1-C6 alkoxy group,
ハロゲノ C1〜C6アルコキシ基、 フエニル C1〜C6アルコキシ基（このフエニル C1〜C6アルコキシ基のフエニル基は、 ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6アルコキシ基からなる群より 選ばれる基で 1〜3個置換されていてもよい。）、 Halogeno C1-C6 alkoxy group, phenyl C1-C6 alkoxy group (the phenyl group of this phenyl C1-C6 alkoxy group is a group selected from the group consisting of a halogeno group, a C1-C6 alkanoleno group, a hydroxyl group, and a C1-C6 alkoxy group. 1 to 3 may be substituted).
フエノキシ基（このフエノキシ基は、ハロゲノ基、 C1〜C6アルキル基、水酸基及び C1 〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、 アミノ基、 A phenoxy group (this phenoxy group may be substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group), an amino group,
モノ（C1〜C6アルキル）アミノ基、 Mono (C1-C6 alkyl) amino group,
ジ（C1〜C6アルキル）アミノ基、 Di (C1-C6 alkyl) amino group,
C 2〜 C 6アル力ノィルァミノ基、 C 2 to C 6 al force neuroamino group,
ベンゾィルァミノ基（このべンゾィルァミノ基のベンゾィル基は、ハロゲノ基、 C1〜C6 アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個 置換されていてもよい。）、 A benzoylamino group (the benzoyl group of the benzoylamino group may be substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group);
ベンジルァミノ基（このベンジルァミノ基のベンジル基は、ハロゲノ基、 C1〜C6アル キル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換 されていてもよい。）、 A benzylamino group (the benzyl group of the benzylamino group may be substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group);
C1—C6アルキルチオ基、  C1-C6 alkylthio group,
C 1〜 C 6アルキルスルフィエル基、  A C1-C6 alkylsulfier group,
C 1〜 C 6アルキルスルホニル基、 フエ二ルチオ基（このフエ二ルチオ基のフエニル基は、ハロゲノ基、 C1〜C6ァノレキノレ 基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換され ていてもよい。）、 A C1-C6 alkylsulfonyl group, A phenylthio group (the phenyl group of this phenylthio group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 anolenoquinol group, a hydroxyl group and a C1-C6 alkoxy group. ),
フエニルスルフィニル基（このフエニルスルフィニル基のフエニル基は、ハロゲノ基、 C ；!〜 C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1 〜3個置換されていてもよい。）、及び Phenylsulfinyl group (the phenyl group of this phenylsulfinyl group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, C;! To C6 alkyl group, hydroxyl group and C1 to C6 alkoxy group) Good), and
フエニルスルホニル基（このフエニルスルホニル基のフエニル基は、ハロゲノ基、 C1 〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1 〜3個置換されていてもよい。 )； A phenylsulfonyl group (the phenylsulfonyl group of this phenylsulfonyl group may be substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group. );
からなる群より選ばれる基で 1〜3個置換された C1〜C6アルキル基である請求項 2 に記載の化合物、その塩又はそれらの溶媒和物。 The compound according to claim 2, a salt thereof, or a solvate thereof, which is a C1-C6 alkyl group substituted with 1 to 3 groups selected from the group consisting of:
一般式（I)中の R2が、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C3〜C7 シクロアルキル C；!〜 C 6アルキル基、フエニル C1〜C6アルキル基（このフエニル C1 〜C6アルキル基のフエニル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1 〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、 5 又は 6員の芳香族複素環基 C1〜C6アルキル基 (この芳香族複素環基は、ハロゲ ノ基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれ る基で 1〜3個置換されていてもよい。）、 4〜7員の脂肪族複素環基 C1〜C6アル キル基 (この脂肪族複素環基は、ハロゲノ基、 C1〜C6アルキル基、水酸基及び C1 〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、 4 〜 7員の脂肪族複素環基 CO— C 1〜C6アルキル基 (この脂肪族複素環基は、ハ ロゲノ基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選 ばれる基で 1〜3個置換されていてもよい。）、 ヒドロキシ C1〜C6アルキル基、 C；!〜 C6アルコキシ C1〜C6アルキル基、フエノキシ C1〜C6アルキル基（このフエノキシ 基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6アルコキシ基からなる 群より選ばれる基で 1〜3個置換されていてもよい。）、ァミノ C1〜C6アルキル基、 C2 〜 C 6アル力ノィノレアミノー C 1〜 C 6アルキル基、 C 1〜 C 6アルキルチオ C；!〜 C 6ァ ノレキノレ基、 C1〜C6アルキルスルホニル C1〜C6アルキル基、又は C3〜C7シクロア ルキル基である請求項 1に記載の化合物、その塩又はそれらの溶媒和物。 R 2 in the general formula (I) is a C1-C6 anolenoquinole group, a halogeno C1-C6 alkyl group, a C3-C7 cycloalkyl C;! -C 6 alkyl group, a phenyl C1-C6 alkyl group (this phenyl C1-C6 The phenyl group of the alkyl group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1 to C6 anolenoquinole group, a hydroxyl group and a C1 to C6 alkoxy group. Aromatic heterocyclic group C1-C6 alkyl group (This aromatic heterocyclic group is substituted with one to three groups selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group. A 4- to 7-membered aliphatic heterocyclic group C1-C6 alkyl group (this aliphatic heterocyclic group comprises a halogeno group, a C1-C6 alkyl group, a hydroxyl group, and a C1-C6 alkoxy group) 1 to 3 groups may be substituted with a group selected from the group)), 4 to 7-membered fat Heterocyclic group CO—C1-C6 alkyl group (This aliphatic heterocyclic group is substituted with a group selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group. Hydroxy C1-C6 alkyl group, C;! -C6 alkoxy C1-C6 alkyl group, phenoxy C1-C6 alkyl group (this phenoxy group is a halogeno group, C1-C6 anolenoquine group, hydroxyl group and 1 to 3 groups may be substituted with a group selected from the group consisting of C1 to C6 alkoxy groups.), Amino C1 to C6 alkyl groups, C2 to C6 alkylenoreamino-C1 to C6 alkyl groups, C1 ~ C 6 alkylthio C;! ~ C 6 alkylenole group, C1-C6 alkylsulfonyl C1-C6 alkyl group, or C3-C7 cycloa 2. The compound according to claim 1, which is an alkyl group, a salt thereof, or a solvate thereof.
[5] R2が、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C3〜C7シクロアルキル C 1〜 C 6アルキル基、フエニル C；!〜 C 6アルキル基（このフエニル C；!〜 C 6アルキノレ 基のフエニル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6アルコキ シ基からなる群より選ばれる基で 1〜3個置換されていてもよい。）、 4〜7員の脂肪族 複素環基 CO— C1〜C6アルキル基 (この脂肪族複素環基は、ハロゲノ基、 Cl〜 C6ァノレキノレ基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3 個置換されていてもよい。）、 C；!〜 C6アルキルチオ C1〜C6アルキル基、又は C3〜 C7シクロアルキル基である請求項 4に記載の化合物、その塩又はそれらの溶媒和物[5] R 2 is a C1-C6 anolenoquinole group, a halogeno C1-C6 alkyl group, a C3-C7 cycloalkyl C1-C6 alkyl group, a phenyl C;!-C6 alkyl group (this phenyl C;!-C The phenyl group of the 6 alkynole group may be substituted with 1 to 3 groups selected from the group consisting of a halogeno group, a C1 to C6 alkenyl group, a hydroxyl group and a C1 to C6 alkoxy group. An aliphatic heterocyclic group of CO—C1-C6 alkyl group (this aliphatic heterocyclic group is a group selected from the group consisting of a halogeno group, a Cl-C6 alkanoleno group, a hydroxyl group and a C1-C6 alkoxy group. Or C;! To C6 alkylthio C1 to C6 alkyl group, or C3 to C7 cycloalkyl group, or a salt thereof, or a solvate thereof.
〇 Yes
[6] R2が、 C1〜C6アルキル基、フルォロ C1〜C6アルキル基、 C3〜C7シクロアルキル メチル基、ベンジル基（このベンジル基は、ハロゲノ基、 C1〜C6アルキル基、水酸基 及び C1〜C6アルコキシ基からなる群より選ばれる基で 1〜3個置換されていてもよ い。）、メチルチオ C1〜C6アルキル基又は C3〜C7シクロアルキル基である請求項 5 に記載の化合物、その塩又はそれらの溶媒和物。 [6] R 2 is a C1-C6 alkyl group, a fluoro C1-C6 alkyl group, a C3-C7 cycloalkylmethyl group, a benzyl group (this benzyl group is a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 1 to 3 groups may be substituted with a group selected from the group consisting of alkoxy groups.), A methylthio C1-C6 alkyl group or a C3-C7 cycloalkyl group, or a salt thereof, or a salt thereof, Their solvates.
[7] R2が、メチル基、ェチル基、 n プロピル基、イソプロピル基、 n ブチル基、イソブチ ノレ基、 tert ブチル基、 n ペンチル基、 3—メチルー n ブチル基、 n へキシル基 、 4—メチル n ペンチル基、 3—フルォロ一 n プロピル基、 4—フルォロ一 n ブ チノレ基、 4—フルオロー 3—メチル n ブチル基、 5—フルオロー n ペンチル基、 6—フルオロー n へキシル基、シクロプロピルメチル基、シクロブチルメチル基、シク 口ペンチルメチル基、シクロへキシルメチル基、ベンジル基（このベンジル基は、ハロ ゲノ基、 C1〜C6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ば れる基で 1〜3個置換されてもよい。）、メチルチオェチル基、メチルチオプロピル基、 シクロプロピル基、シクロブチル基、シクロペンチル基又はシクロへキシル基である請 求項 6に記載の化合物、その塩又はそれらの溶媒和物。 [7] R 2 is a methyl group, an ethyl group, an n propyl group, an isopropyl group, an n butyl group, an isobutynol group, a tert butyl group, an n pentyl group, a 3-methyl-n butyl group, an n hexyl group, a 4- Methyl n pentyl group, 3-Fluoro-n-propyl group, 4-Fluoro-n butynole group, 4-Fluoro-3-methyl-n-butyl group, 5-Fluoro-n-pentyl group, 6-Fluoro-n-hexyl group, Cyclopropylmethyl Group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, benzyl group (this benzyl group is a group selected from the group consisting of a halogeno group, a C1-C6 alkyl group, a hydroxyl group and a C1-C6 alkoxy group) 1 to 3 may be substituted with a methylthioethyl group, a methylthiopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. 7. The compound according to claim 6, which is a thio group, a salt thereof, or a solvate thereof.
[8] R2が、 3—フノレオ口一 n プロピノレ基、 4—フノレオ口一 n ブチノレ基、 4—フノレオロー 3 —メチノレ一 n ブチノレ基、 5—フノレオロー n ペンチノレ基、 6—フノレオロー n へキシ ノレ基、シクロプロピルメチル基、シクロブチルメチル基、シクロペンチルメチル基、ベン ジル基（このベンジル基は、ハロゲノ基、 C1〜C6ァノレキノレ基、水酸基及び C1〜C6 アルコキシ基からなる群より選ばれる基で 1〜3個置換されてもよい。）、メチルチオェ チノレ基、メチルチオプロピル基、シクロプロピル基、シクロブチル基、シクロペンチル 基又はシクロへキシル基である請求項 7に記載の化合物、その塩又はそれらの溶媒 和物。 [8] R 2 is a 3-funoleoline n-propinole group, 4-funoleole n-butinore group, 4-funoleolo 3 —methylolene n-butinole group, 5-funoleolone n-pentinole group, 6-funoleolone n-hexenole Group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, A dil group (this benzyl group may be substituted by 1 to 3 groups selected from the group consisting of a halogeno group, a C1-C6 anolenoquine group, a hydroxyl group and a C1-C6 alkoxy group), a methylthioethylenol group, a methylthiopropyl group 8. The compound according to claim 7, a salt thereof or a solvate thereof, which is a group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
[9] 一般式 (I)中の R1が、水素原子、メチル基又はェチル基である請求項 1〜8のいずれ 力、 1項に記載の化合物、その塩又はそれらの溶媒和物。 [9] The compound according to any one of claims 1 to 8, wherein R 1 in the general formula (I) is a hydrogen atom, a methyl group or an ethyl group, a salt thereof, or a solvate thereof.
[10] R1が水素原子である請求項 9に記載の化合物、その塩又はそれらの溶媒和物。 [10] The compound according to claim 9, a salt thereof or a solvate thereof, wherein R 1 is a hydrogen atom.
[11] 一般式 (I)中の環 Aが、ベンゼン環、フラン環、チォフェン環、ピロール環、ピリジン環[11] Ring A in general formula (I) is a benzene ring, furan ring, thiophene ring, pyrrole ring, pyridine ring
、ピリダジン環、ピリミジン環又はピラジン環である請求項 1〜； 10のいずれ力、 1項に記 載の化合物、その塩又はそれらの溶媒和物。 Or a pyridazine ring, a pyrimidine ring or a pyrazine ring. The compound according to any one of claims 1 to 10, the salt thereof, or a solvate thereof.
[12] 環 Aが、ベンゼン環である請求項 11に記載の化合物、その塩又はそれらの溶媒和 物。 [12] The compound, a salt thereof or a solvate thereof according to claim 11, wherein Ring A is a benzene ring.
[13] 環 Aが、 1 , 4 フエ二レン基である請求項 12に記載の化合物、その塩又はそれらの 溶媒和物。  [13] The compound, salt or solvate thereof according to claim 12, wherein ring A is a 1,4-phenylene group.
[14] 一般式（I)中の Xが、水素原子であるか、或いは、同一又は異なって、ハロゲノ基、 C ；!〜 C 6アルキル基、水酸基及び C1〜C6アルコキシ基からなる群より選ばれる 1〜3 個の基である請求項 1〜； 13のいずれ力、 1項に記載の化合物、その塩又はそれらの溶 媒和物。  [14] X in the general formula (I) is a hydrogen atom, or the same or different and selected from the group consisting of a halogeno group, C;! To C 6 alkyl group, a hydroxyl group, and a C 1 to C 6 alkoxy group 14. The compound according to any one of claims 1 to 13, wherein the compound is a salt thereof or a solvate thereof.
[15] 一般式 (I)中の Yが、上記の式 (a)、 （c)、 （e)、 （f)、 （h)、 (i)又は (v)で表される基で ある請求項 1〜； 14のいずれ力、 1項に記載の化合物、その塩又はそれらの溶媒和物。  [15] Y in the general formula (I) is a group represented by the above formula (a), (c), (e), (f), (h), (i) or (v) The power according to any one of claims 1 to 14, the compound according to claim 1, a salt thereof, or a solvate thereof.
[16] Ύ 式 (a)で表される基である請求項 15に記載の化合物、その塩又はそれらの溶 媒和物。  [16] The compound according to claim 15, which is a group represented by formula (a), a salt thereof, or a solvent thereof.
[17] Y力 S、下記の式 (y)又は（z)  [17] Y force S, following formula (y) or (z)
[化 3]  [Chemical 3]
Figure imgf000164_0001
(式中、 R3y及び R3zは、同一又は異なって、水素原子又は C1〜C6アルキル基を示 し、
Figure imgf000164_0001
(Wherein R 3y and R 3z are the same or different and each represents a hydrogen atom or a C1-C6 alkyl group,
R4y及び R5yは、同一又は異なって、水素原子、 C1〜C6ァノレキノレ基、ハロゲノ C；!〜 C6ァノレキノレ基、 C1〜C6アルコキシ C1〜C6アルキル基、 C3〜C7シクロアルキル 基又は C 3〜 C 7シクロアルキル C；!〜 C 6アルキル基を示し、 R 4y and R 5y are the same or different and are a hydrogen atom, C1-C6 anolenoquinole group, halogeno C;! -C6 alkenoquinole group, C1-C6 alkoxy C1-C6 alkyl group, C3-C7 cycloalkyl group or C3- C 7 cycloalkyl C;! To C 6 alkyl group,
R6y、 R6z、 R7y、 R7z、 R8y、 R8z、 R9y及び R9zは、同一又は異なって、水素原子、ハロゲ ノ基、 C1〜C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、 C1〜C6アルコキシ C；!〜 C6ァノレキノレ基、水酸基、 C1〜C6アルコキシ基、ハロゲノ C1〜C6アルコキシ基又は C1〜C6アルコキシ C1〜C6アルコキシ基を示し、 R 6y , R 6z , R 7y , R 7z , R 8y , R 8z , R 9y and R 9z are the same or different and are a hydrogen atom, a halogeno group, a C1-C6 anorequinole group, a halogeno C1-C6 alkyl group, C1-C6 alkoxy C;! -C6 alkenoquinole group, hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy C1-C6 alkoxy group,
R15z、 R16z及び R17zは、同一又は異なって、水素原子、ハロゲノ基、 C1〜C6アルキ ル基、ハロゲノ C1〜C6アルキル基、 C 1〜C6アルコキシ C1〜C6アルキル基、水酸 基、 C1〜C6アルコキシ基、ハロゲノ C1〜C6アルコキシ基又は C1〜C6アルコキシR 15z , R 16z and R 17z are the same or different and each represents a hydrogen atom, a halogeno group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy C1-C6 alkyl group, a hydroxyl group, C1-C6 alkoxy group, halogeno C1-C6 alkoxy group or C1-C6 alkoxy group
C1〜C6アルコキシ基を示す。）で表される基である請求項 1〜； 16のいずれ力、 1項に 記載の化合物、その塩又はそれらの溶媒和物。 A C1-C6 alkoxy group is shown. The compound represented by any one of claims 1 to 16, the salt thereof, or a solvate thereof.
[18] 式 (y)及び (z)中の R3y及び R3zが、同一又は異なって、水素原子又はメチル基である 請求項 17に記載の化合物、その塩又はそれらの溶媒和物。 18. The compound according to claim 17, a salt thereof, or a solvate thereof, wherein R 3y and R 3z in the formulas (y) and (z) are the same or different and are a hydrogen atom or a methyl group.
[19] 式 (y)及び (z)中の R6y、 R6z、 R7y、 R7\ R8y、 R8\ R9y及び R9zが、同一又は異なって[19] R 6y , R 6z , R 7y , R 7 \ R 8y , R 8 \ R 9y and R 9z in formulas (y) and (z) are the same or different
、水素原子又は C1〜C6アルキル基である、請求項 17又は 18に記載の化合物、そ の塩又はそれらの溶媒和物。 The compound, its salt, or those solvates of Claim 17 or 18 which are a hydrogen atom or a C1-C6 alkyl group.
[20] Y力 式（z)で表される基である請求項 17〜； 19のいずれか 1項に記載の化合物、そ の塩又はそれらの溶媒和物。 [20] Y force The group represented by formula (z), the compound according to any one of claims 17 to 19; a salt thereof, or a solvate thereof.
[21] 式 (z)中の R15z、 R16z及び R17zが、同一又は異なって、水素原子、ハロゲノ基、 Cl〜[21] R 15z , R 16z and R 17z in the formula (z) are the same or different and each represents a hydrogen atom, a halogeno group, Cl to
C6ァノレキノレ基、ハロゲノ C1〜C6アルキル基、水酸基又は C1〜C6アルコキシ基で ある請求項 20に記載の化合物、その塩又はそれらの溶媒和物。 21. The compound according to claim 20, a salt thereof, or a solvate thereof, which is a C6 alkenoquinole group, a halogeno C1-C6 alkyl group, a hydroxyl group, or a C1-C6 alkoxy group.
[22] Y力 式 (e)又は (V)で表される基である請求項 15に記載の化合物、その塩又はそ れらの溶媒和物。 [22] Y-force The compound according to claim 15, which is a group represented by formula (e) or (V), a salt thereof, or a solvate thereof.
[23] 下記の式（II一;!）〜（II 44) [23] The following formula (II I ;!) to (II 44)
[化 4] ( 8 τ - I I ) ( z τ - I i ) ( 9 ΐ - I I ) [Chemical 4] (8 τ-II) (z τ-I i) (9 ΐ-II)
Figure imgf000166_0001
Figure imgf000166_0001
£66£L0/L00ZdT/13d 1791- Z89Z.0/800Z OAV £ 66 £ L0 / L00ZdT / 13d 1791- Z89Z.0 / 800Z OAV
Figure imgf000167_0001
Figure imgf000167_0002
Figure imgf000167_0003
Figure imgf000167_0001
Figure imgf000167_0002
Figure imgf000167_0003
[化 10]
Figure imgf000168_0001
[Chemical 10]
Figure imgf000168_0001
( I 1 - 37) ( I 1 - 38) ( I 1 - 39) (I 1-37) (I 1-38) (I 1-39)
Figure imgf000168_0002
Figure imgf000168_0002
Figure imgf000168_0003
Figure imgf000168_0003
( I 1 - 43) ( I 1 - 44)  (I 1-43) (I 1-44)
で表されるいずれ力、 1つの化合物、その塩又はそれらの溶媒和物。 Any one of the forces represented by: one compound, a salt thereof or a solvate thereof.
上記の式（II 1)、 (11— 2)、（11— 3)、（11— 4)、（11— 5)、（11— 6)、（11— 7)、 (II 8The above formulas (II 1), (11-2), (11-3), (11-4), (11-5), (11-6), (11-7), (II 8
)、（11— 9)、 (II 10)、 (II 11)、 (Π— 12)、 (11—13)、（11—14)、（11—15)、 (II 16)、（II 17)、（II 18)、（II 19)、（II 20)、（II 21)、（II 22)、（II 23), (11-9), (II 10), (II 11), (Π-12), (11-13), (11-14), (11-15), (II 16), (II 17 ), (II 18), (II 19), (II 20), (II 21), (II 22), (II 23
)、（II 24)又は（II 25)で表される請求項 23に記載の化合物、その塩又はそれら の溶媒和物。 24) A compound, a salt thereof or a solvate thereof according to claim 23, which is represented by (II), (II 24) or (II 25).
下記の below
4-[6-[(3, 4ージクロ口ベンジル）ァミノ]イミダゾ [1, 2— b]ピリダジンー3 ィル] N— [2—（ジメチルァミノ）ェチル]ベンズアミド、  4- [6-[(3,4-dichlorodibenzyl) amino] imidazo [1,2-b] pyridazine-3-yl] N— [2- (dimethylamino) ethyl] benzamide,
4- [6 - [(、: /クロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3- —ィルコ 4- [6-[(,: / Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3- —ilco
N- - (2—ァミノェチル）ベンズアミド、 N--(2-Aminoethyl) benzamide,
4- [6 - [(、: /クロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3- —ィルコ 4- [6-[(,: / Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3- —ilco
N- -[2— (ィ 'ソプロピルァミノ）ェチル]ベンズアミド、 N--[2— (So'propylamino) ethyl] benzamide,
4- [6 - [(、: /クロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3- —ィルコ 4- [6-[(,: / Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3- —ilco
N- -[2-(> ；メチルァミノ）ェチル]ベンズアミド、 N-[2-(>; methylamino) ethyl] benzamide,
4- [6— [(、: /クロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3- —ィル] N— [2—（ジメチルァミノ）ェチル] N メチルベンズアミド、 4- [6 — [(,: / Chlopropylmethyl) amino] imidazo [1,2-b] pyridazine 3- —yl] N— [2- (dimethylamino) ethyl] N methylbenzamide,
( ± )— 4— [ 6 [(シクロプロピルメチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3 ィ ル]—N—[(1R, 2R) -2- (ジメチルァミノ）シクロへキシル]ベンズアミド、  (±) — 4— [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3-yl] —N — [(1R, 2R) -2- (dimethylamino) cyclohexyl] benzamide,
[ (3R)— 3— (ジメチノレアミノ）ピロリジン一 1—ィル] = [4— [6— [ (シクロプロピルメチ ル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン— 3 ィル]フエニル] =ケトン、  [(3R) — 3— (Dimethylolamino) pyrrolidine 1-yl] = [4— [6— [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine-3 yl] phenyl] = Ketones,
( ± )— 4— [ 6 [(シクロプロピルメチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3 ィ ル] N— [ (1R, 2R)-2- (ジメチルァミノ）シクロペンチル]ベンズアミド、  (±) — 4— [6 [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3 yl] N— [(1R, 2R) -2- (dimethylamino) cyclopentyl] benzamide,
[ (2R)— 2— [ [ (3R)— 3—フルォロピロリジン一 1—ィル]メチル]ピロリジン一 1—ィ ル] = [4— [6— [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3—ィ ルコフエ-ル] =ケ -トン、  [(2R) — 2— [[(3R) — 3-Fluoropyrrolidine 1-yl] methyl] pyrrolidine 1-yl] = [4— [6— [(Cyclopropylmethyl) amino] imidazo [1, 2— b] pyridazine 3— lycofer] = keton,
4- [6- [(シクロプロピルメチル）ァミノ ']イミダゾ [ 1 , 2— b]ピリダジン 3 ィル] - 4- [6- [(Cyclopropylmethyl) amino '] imidazo [1, 2— b] pyridazine 3 yl]-
N- - [2— (ジメチノ 'レ ミノ）ェチノレ] 2- -メチルベンズアミド、 N--[2— (Dimethino'remino) ethinole] 2- -methylbenzamide,
4- [6- [(シクロプロピルメチル）ァミノ ']イミダゾ [ 1 , 2— b]ピリダジン 3 ィル] - 4- [6- [(Cyclopropylmethyl) amino '] imidazo [1, 2— b] pyridazine 3 yl]-
N- - [2— (ジメチノ 'レアミノ）ェチル ] 3- -メチルベンズアミド、 N-[2— (Dimethino'reamino) ethyl] 3-methylbenzamide,
5- [6- [(シクロプロピルメチル）ァミノ ']イミダゾ [ 1 , 2— b]ピリダジン 3 ィル] - 5- [6- [(Cyclopropylmethyl) amino '] imidazo [1, 2— b] pyridazine 3 yl]-
N- - [2— (ジメチノ 'レアミノ）ェチル]チォフェン 2—カルボキサミド、 N-[2— (Dimethino'reamino) ethyl] thiophene 2-carboxamide,
4- [6- [(シクロプロピルメチル）ァミノ ']イミダゾ [ 1 , 2— b]ピリダジン 3 ィル] - 4- [6- [(Cyclopropylmethyl) amino '] imidazo [1, 2— b] pyridazine 3 yl]-
N- - [2— [(3R)- -3 フノレ才ロピロリジ ：ン 1 ィル]ェチル]ベンズアミド、 N--[2— [(3R)--3 Funore age lopyrrolid: 1 yl] ethyl] benzamide,
4- [6- [(シクロプロピルメチル）ァミノ ']イミダゾ [ 1 , 2— b]ピリダジン 3 ィル] 2 4- [6- [(Cyclopropylmethyl) amino '] imidazo [1, 2— b] pyridazine 3 yl] 2
7ルォロー N— [3—（ジメチノレアミノ; 1プロパン 2—ィル]ベンズアミド、 7Lulow N— [3 -— (Dimethylolamino; 1propane 2-yl] benzamide,
4- [6- [(シクロプロピルメチル）ァミノ ']イミダゾ [ 1 , 2— b]ピリダジン 3 ィル] 2 4- [6- [(Cyclopropylmethyl) amino '] imidazo [1, 2— b] pyridazine 3 yl] 2
7ルォロー N—メチルー N— [2—（、 メチルァミノ）ェチル]ベンズアミド、 7Lulow N-Methyl-N— [2-(, Methylamino) ethyl] benzamide,
4- [6- [(シクロプロピルメチル）ァミノ ']イミダゾ [ 1 , 2— b]ピリダジン 3—ィル] 2 4- [6- [(Cyclopropylmethyl) amino '] imidazo [1, 2— b] pyridazine 3-yl] 2
7ルォロー N— [[(2S) 1 メチルピロリジン— 2—ィル]メチル]ベンズアミド、7Lulow N — [[(2S) 1 Methylpyrrolidine-2-yl] methyl] benzamide,
4- [6- [(シクロプロピルメチル）ァミノ ']イミダゾ [ 1 , 2— b]ピリダジン 3 ィル] 24- [6- [(Cyclopropylmethyl) amino '] imidazo [1, 2— b] pyridazine 3 yl] 2
7ルォロー N—メチノレー N— (1—メ レピロリジン 3—ィル）ベンズアミド、7Lulow N—Methinore N— (1-Methylpyrrolidine 3-yl) benzamide,
4- [6- [(シクロプロピルメチル）ァミノ ']イミダゾ [ 1 , 2— b]ピリダジン 3 ィル] 24- [6- [(Cyclopropylmethyl) amino '] imidazo [1, 2— b] pyridazine 3 yl] 2
7ルォロー N— [[(2S, 4S)— 4 フ 'ルォ口ピロリジン 2 ィノレ]メチノレ]ベンズァ ミド、 7Lulow N— [[(2S, 4S) — 4 Fluoropyrrolidine 2]] Minole] Benza Mid,
[ (2R)— 2 (ピロリジン一 1—ィルメチル）ピロリジン一 1—ィル] = [4— [6 [ (シク ロブチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン— 3—ィル]フエニル] =ケトン、 [(2R) — 2 (Pyrrolidine 1-ylmethyl) pyrrolidine 1-yl] = [4— [6 [(Cyclobutyl) amino] imidazo [1, 2— b] pyridazine-3-yl] phenyl] = Ketone,
4 [6—（シクロブチノ 'レアミノ)イミダゾ [1, 2— b]ピリダ:ジン— 3—ィルコ— 2. フルォ ロー N— [2—（ジメチルァミノ）ェチル]ベンズアミド、 4 [6 -— (Cyclobutino'reamino) imidazo [1,2-b] pyrida: zin-3-ylco— 2. fluoro N— [2- (dimethylamino) ethyl] benzamide,
4 [6 （シクロブチノ 'レアミノ)イミダゾ [1, 2— b]ピリダ:ジン— 3 ィルコ— 2. フルォ ロー N—[2—（ジェチ レアミノ）ェチル]ベンズアミド、  4 [6 (Cyclobutino'reamino) imidazo [1,2-b] pyrida: gin-3ylco- 2. fluoro N- [2- (jetylamino) ethyl] benzamide,
4 [6— [(シクロブヲ -ル）ァミノ]イミダゾ [1, 2— b]ピリダジン— 3—ィル] 2—フル オロー N— [2—ピロリジン 1 ィルェチル]ベンズァミド、  4 [6 — [(Cyclobufo-l) amino] imidazo [1,2-b] pyridazine-3-yl] 2-fluoro N- [2-pyrrolidine 1-ilethyl] benzamide,
4 [6 [(シクロプロピルメチル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル ] 2 -フルォロ N— [(2S)—ピロリジン一 2—ィルメチル]ベンズアミド、  4 [6 [(Cyclopropylmethyl) amino] imidazo [1,2-b] pyridazine 3 yl] 2 -Fluoro N— [(2S) -Pyrrolidine-2-ylmethyl] benzamide,
4-[6-[(3-クロ口ベンジル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3 ィル]― N  4- [6-[(3-Chlorobenzyl) amino] imidazo [1,2-b] pyridazine 3-yl]-N
[2—（ジメチルァミノ）ェチル]ベンズアミド、及び  [2- (dimethylamino) ethyl] benzamide, and
4 [6— [(4 メトキシベンジル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル]—N  4 [6— [(4 Methoxybenzyl) amino] imidazo [1, 2— b] pyridazine 3 yl] —N
[2—（ジメチルァミノ）ェチル]ベンズアミド、  [2- (dimethylamino) ethyl] benzamide,
力、らなる群より選ばれるいずれ力、 1つの化合物、その塩又はそれらの溶媒和物。  Force, any force selected from the group consisting of one compound, a salt thereof or a solvate thereof.
[26] 下記の [26] Below
2—フルォロ 4— [6— [ (4—フルォロブチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 2—Fluoro 4— [6— [(4-Fluorobutyl) amino] imidazo [1, 2 — b] pyridazine
3 -ィル] N— [[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチル]ベンズアミ ド、、 3 -yl] N — [[(2S, 4R) — 4 fluoropyrrolidine-2-yl] methyl] benzamide,
4 [6— [(4—フルォロブチル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3—ィル]—N 4 [6— [(4-Fluorobutyl) amino] imidazo [1, 2— b] pyridazine 3-yl] —N
— [[(2S, 4R)— 4 フルォロピ口リジン一 2 ィル]メチル]ベンズアミド、 — [[(2S, 4R) — 4 Fluoropyral lysine mono-2-yl] methyl] benzamide,
2—フルオロー 4 [6— [(3—フルォロプロピル）ァミノ]イミダゾ [1, 2— b]ピリダジン 2-Fluoro-4 [6— [(3-Fluoropropyl) amino] imidazo [1, 2— b] pyridazine
— 3 ィル] N— [[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチノレ]ベンズァ ミド、 — 3 yl] N— [[(2S, 4R) — 4 Fluoropyrrolidine 1 yl] methinole] benzamide,
N-[[(2S, 4R)—4 フルォロピロリジン— 2 ィル]メチル]—4— (6— [[3— (メチ ルチオ）プロピル]ァミノ]イミダゾ [1 , 2— b]ピリダジン 3 ィル）ベンズアミド、 N-[[(2S, 4R) —4 Fluoropyrrolidine—2yl] methyl] —4— (6— [[3— (methylthio) propyl] amino] imidazo [1, 2— b] pyridazine 3 Yil) benzamide,
2 フルオロー N— [[(2S, 4R)—4 フルォロピロリジン一 2 ィノレ]メチル ]—4— ( 6— [ [2 （メチルチオ）ェチル]ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3 ィル）ベン ズアミド、 2 Fluoro-N — [[(2S, 4R) —4 Fluoropyrrolidine-1-2inole] methyl] —4— ( 6 — [[2 (Methylthio) ethyl] amino] imidazo [1,2-b] pyridazine 3yl) benzamide,
4— [6— [ (5—フルォロ pentィル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン— 3—ィル]― 4— [6— [(5-Fluoropentyl) amino] imidazo [1, 2— b] pyridazine— 3—yl] —
N-[[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチル]ベンズアミド、 N-[[((2S, 4R) — 4 fluoropyrrolidine-2-yl] methyl] benzamide,
2—フルォロ— 4— [6— [( 5—フルォロ pentィル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 2—Fluoro— 4— [6— [(5-Fluoropentyl) amino] imidazo [1, 2— b] pyridazine
— 3 ィル] N— [[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチノレ]ベンズァ ミド、 — 3 yl] N— [[(2S, 4R) — 4 Fluoropyrrolidine 1 yl] methinole] benzamide,
2—フルォロ 4— [6— [ (6—フルォ口へキシル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン — 3 ィル] N— [[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチノレ]ベンズァ ミド、  2—Fluoro 4— [6— [(6-Fluorohexyl) amino] imidazo [1, 2 — b] Pyridazine — 3 yl] N— [[((2S, 4R) — 4 Fluoropyrrolidine 1 2 Il] Mechinore] Benzamide,
4 [6— [(6 フルォ口へキシル）ァミノ]イミダゾ [1, 2—b]ピリダジンー3 ィル] N-[[(2S, 4R)— 4 フルォロピロリジン一 2 ィル]メチル]ベンズアミド、  4 [6— [(6 Fluorohexyl) amino] imidazo [1, 2—b] pyridazine-3 yl] N-[[(2S, 4R) — 4 Fluoropyrrolidine 1 2 yl] methyl] benzamide ,
2 フルォロ一 N— [[(2R, 3S)— 3 メトキシピロリジン一 2 ィル]メチル ]—4— (6 一 [ [2—（メチルチオ）ェチル]ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3—ィル）ベンズ アミド、 2 Fluoro N — [[(2R, 3S) — 3 Methoxypyrrolidine 1 2 yl] methyl] —4— (6 1 [[2- (Methylthio) ethyl] amino] imidazo [1, 2— b] pyridazine 3 —Yel) Benz Amido,
2—フルォロ 4— [6— [ (4 フルォロブチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 3 ィル]—N—[[(2R, 3S)— 3 メトキシピロリジンー2 ィル]メチル]ベンズアミド  2—Fluoro 4— [6— [(4 Fluorobutyl) amino] imidazo [1, 2 — b] pyridazine 3 yl] —N — [[(2R, 3S) — 3 methoxypyrrolidine-2 yl] methyl] benzamide
2 フルオロー 4 [6— [(3 フルォロプロピル）ァミノ]イミダゾ [1, 2— b]ピリダジン 3 ィル]—N—[[(2R, 3S)— 3 メトキシピロリジンー2 ィル]メチル]ベンズァ ミド、 2 fluoro-4 [6 — [(3 fluoropropyl) amino] imidazo [1, 2— b] pyridazine 3 yl] —N — [[(2R, 3S) — 3 methoxypyrrolidine-2 yl] methyl] benzamide,
2—フルォロ 4 [6 [ (4—フルォロブチル）ァミノ]イミダゾ [ 1 , 2— b]ピリダジン 2—Fluoro 4 [6 [(4-Fluorobutyl) amino] imidazo [1, 2 — b] pyridazine
3 ィル] N— [[( 2 S )— 1 メチルピロリジン 2 ィル]メチル]ベンズアミド、及び 2—フルォロ 4— [6— [ (4 フルォロ 3 メチルブチル）ァミノ]イミダゾ [ 1 , 2—b ]ピリダジン一 3 ィル] N— [ [ ( 2 S , 4R)— 4 フルォロピ口リジン一 2 ィル]メチ ノレ]ベンズアミド 3yl] N — [[((2S) —1methylpyrrolidine 2yl] methyl] benzamide and 2-fluoro 4- [6 — [(4 fluoro 3-methylbutyl) amino] imidazo [1, 2-b] 1 pyridazine 3 N] N— [[(2 S, 4R) — 4 fluoropirine lysine 1 2 yl] methylol] benzamide
からなる群より選ばれるいずれ力、 1つの化合物、その塩又はそれらの溶媒和物。 請求項;!〜 26のいずれか 1項に記載の化合物、その塩又はそれらの溶媒和物を有 効成分として含有する医薬。 Any force selected from the group consisting of: one compound, a salt thereof, or a solvate thereof. A compound according to any one of claims 26 to 26, a salt thereof, or a solvate thereof. A medicine containing as an active ingredient.
[28] 請求項;!〜 26のいずれか 1項に記載の化合物、その塩又はそれらの溶媒和物を有 効成分として含有する TNF産生抑制剤。 [28] A TNF production inhibitor comprising the compound according to any one of claims;! To 26, a salt thereof, or a solvate thereof as an active ingredient.
[29] 請求項;!〜 26のいずれか 1項に記載の化合物、その塩又はそれらの溶媒和物を有 効成分として含有する炎症性疾患及び/又は自己免疫性疾患の治療剤及び/又 は予防剤。 [29] Claims; A therapeutic agent for inflammatory diseases and / or autoimmune diseases comprising the compound, salt or solvate thereof according to any one of! -26 as an active ingredient and / or Is a prophylactic agent.
[30] 請求項;!〜 26のいずれか 1項に記載の化合物、その塩又はそれらの溶媒和物を有 効成分として含有する慢性関節リウマチ治療薬。  [30] A therapeutic agent for rheumatoid arthritis, comprising the compound according to any one of claims;! To 26, a salt thereof, or a solvate thereof as an active ingredient.
[31] 請求項;!〜 26のいずれか 1項に記載の化合物、その塩又はそれらの溶媒和物と、免 疫抑制剤、免疫抑制に用いる抗体、拒絶反応治療薬、抗生物質、非ステロイド性抗 炎症薬（NSAIDs)及びステロイド薬から選択される 1種又は 2種以上を組み合わせ てなる医薬。 [31] Claim;! -26, a compound or salt thereof, or a solvate thereof, an immunosuppressant, an antibody used for immunosuppression, a therapeutic drug for rejection, an antibiotic, a nonsteroid A drug consisting of one or more selected from anti-inflammatory drugs (NSAIDs) and steroids.
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